FGFR4 inhibitor, preparation method therefor and pharmaceutical use thereof

ABSTRACT

Provided are an FGFR4 inhibitor having the structure of formula (I), and a preparation method therefor and the use thereof. The compound has a very strong inhibitory effect on FGFR4 kinase activity and has a very high selectivity, and can be widely used in the preparation of a drug for treating cancers, especially prostate cancer, liver cancer, pancreatic cancer, esophageal carcinomas, gastric cancer, lung cancer, breast cancer, ovarian carcinomas, colon cancer, skin cancer, glioblastomas or rhabdomyosarcomas, and is expected to be developed into a new generation of FGFR4 inhibitor drugs.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.16/348,957, filed May 10, 2019, which is a Section 371 of InternationalApplication No. PCT/CN2017/116186, filed Dec. 14, 2017, which waspublished in the Chinese language on Jun. 28, 2018 under InternationalPublication No. WO 2018/113584 A1, which claims priority under 35 U.S.C.§ 119(b) to Chinese Application No. 201611177188.2, filed Dec. 19, 2016,and Chinese Application No. 201710453749.5, filed Jun. 15, 2017, and thedisclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention belongs to the field of medicament synthesis, andin particular relates to an FGFR4 inhibitor, preparation method andpharmaceutical use thereof.

TECHNICAL BACKGROUND

Fibroblast growth factor (FGF) is a family of 22 structurally relatedpolypeptides with diverse biological activities that can regulate cellproliferation, differentiation and migration, and play a major role inthe process of limb development, angiogenesis, tissue repair, tumorformation and the like. (Eswarakumar et al., 2005 Cytokine Growth FactorRev 16: 139-149 Ornitz and Itoh 2001 Genome Bio 12: Reviews 3005).

The receptors for FGF (FGFR) belong to a family of RPTK of receptortyrosine kinases. Four FGFRs, FGFR1, FGFR2, FGFR3 and FGFR4, have beenidentified to date (Ullrich and Schlessinger, 1990 Cell 61:203). Theinteraction between receptors and the corresponding ligands FGF leads toreceptor dimerization and autophosphorylation, thereby initiatingmultiple downstream signaling cascades including MAPK and AKT (Powers etal., 2000 Endocr Relat Cancer 7: 165-197).

FGFR1-3 has been found to be overexpressed, mutated or translocated in avariety of tumors (including myeloma, breast cancer, stomach cancer,colon cancer, bladder cancer, pancreatic cancer, and hepatocellularcarcinoma), and considered to be driver gene in cancer (Chesi et al.,2001 Blood 97:729-726; Gowardhan et al., 2005 Br J Cancer 92: 320-327;Jaakkola et al., 1993 Int J Cancer 54:378-282; Jang et al., 2001 CancerRes 61: 3541-3543). Some FGFR inhibitors have also been developed in theclinical and preclinical development process. However, previous studieshave shown that FGFR1 can regulate the level of phosphate, so pan-FGFRinhibitors may pose safety concerns.

Hepatocellular carcinoma (CC) is one of the leading causes ofcancer-related deaths in China and is one of the fastest growing cancersevery year (Shariff et al., 2009 Expert Rev Gastroenterol Hepato 13:353-367). Currently, the first-line treatment option is sorafenib, thereare no approved second-line treatment, and there is still a need fortargeted therapy with anti-tumor agents.

Overexpression of FGF19 is present in 5-10% of hepatocellular carcinomapatients, whereas FGFR4 is a dominant FGFR present in human hepatocytes,and its high expression in hepatocytes is found to be associated withthe aggressiveness of hepatocellular tumors. Therefore, FGFR4 plays avery important role in liver cancer. In addition, the interaction ofFGF19 and FGFR4 is also considered to be related to the aggressivenessof other cancers (such as gastric cancer, prostate cancer, lung cancer,colorectal cancer, pancreatic cancer, and ovarian cancer) (Ye et al,2011 Cancer 5304-5313; Xu et al, 2011 BMC Cancer 11:84; Fawdar et al,2013 PNAS 110:12426-12431).

At present, some FGFR inhibitors have entered into the clinical researchstage as anti-tumor drugs, but mostly inhibitors against FGFR1, 2 and 3,with weaker inhibition of FGFR4 activity. The inhibition of FGFR1-3 hason-target side effects such as hyperphosphatenia. Highly selectiveinhibitor of FGFR4 can effectively treat cancer caused by abnormal FGFR4signaling, and can avoid the side effects caused by FGFR1-3 inhibitionsuch as hyperphosphatemia. Highly selective small molecule inhibitorsagainst FGFR4 have significant application prospects in the field ofanti-tumor targeted therapy. Therefore, the development of a novelanti-tumor agent that can selectively target FGFR4 as a good drugcandidate will meet the needs of domestic liver cancer and otheranti-tumor target therapy, and have the advantages of better safety andhigher selectivity.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an FGFR4 inhibitor,preparation method and pharmaceutical use thereof.

The first aspect of the invention provides a compound of formula (I), astereoisomer or a pharmaceutically acceptable salt thereof:

wherein, X₁ is —C(R₇)— or N;

X₂, X₃, and X₅ are each independently selected from the group consistingof —(CR₈)_(n)—, —C(O)—, —N(R₉)—, N and S;

X₄ is C or N;

Z is selected from the group consisting of C₁₋₈ alkylene, C₂₋₈alkenylene, C₂₋₈ alkynylene, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl and 5-10 membered heteroaryl, above groups arefurther optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₈alky, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀,—C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—OC(O)R₁₂,—C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R¹⁴, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and—C₀₋₈—N(R₁₃)—C(O)OR₁₁, above groups are further more optionallysubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀,—C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—OC(O)R₁₂,—C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and—C₀₋₈—N(R₁₃)—C(O)OR₁₁;

R₁ is selected from the group consisting of H, deuterium, C₁₋₈ alkyl,C₁₋₈ alkoxyC₁₋₈ alkyl, C₃₋₈ cycloalkyloxyC₁₋₈ alkyl, C₃₋₈ cycloalkylC₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl and C₁₋₈ alkanoyl;

R₂, R₃, R₄, R₅, R₆ and R₇ are each independently selected from the groupconsisting of H, deuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—S(O)(NR₉)R₁₀, —C₀₋₈—P(O)(R₁₀)₂, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁, or R₂and R₄, R₃ and R₅, R₄ and R₆, R₅ and R₆ are taken together with thedirectly attached carbon atoms to form a C₅₋₁₀ cycloalkyl, 5-10 memberedheterocyclyl, 5-10 membered aryl or 5-10 membered heteroaryl,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈haloalkyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁;

R₈ is selected from the group consisting of H, deuterium, halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—S(O)(NR₉)R₁₀, —C₀₋₈—P(O)(R₁₀)₂,—C₀₋₈—O—R₁₁, —C₀₋₈—C(O)R₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂,—C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and—C₀₋₈—N(R₁₃)—C(O)OR₁₁,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈haloalkyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂and —C₀₋₈—N(R₁₃)—C(O)OR₁₁;

R₉ is selected from the group consisting of H, deuterium, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl and C₁₋₈ alkanoyl, above groups arefurther optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl,—C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂,—C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂and —C₀₋₈—N(R₁₃)—C(O)OR₁₁;

R₁₀ is selected from the group consisting of H, deuterium, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₁₋₈haloalkyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, amino, mono-C₁₋₈alkylamino, di-C₁₋₈ alkylamino and C₁₋₈ alkanoylamino;

R₁₁ is selected from the group consisting of H, deuterium, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl and 5-10 membered heteroaryl, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy,C₁₋₈ alkylthio, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, C₁₋₈ alkylsulfonyl, C₁₋₈ alkylsulfonylamino,amino, mono-C₁₋₈ alkylamino, di-C₁₋₈ alkylamino, ═O or hydroxyl;

R₁₂ is selected from the group consisting of H, deuterium, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 memberedheterocyclyloxy, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₅₋₁₀ aryloxy and5-10 membered heteroaryloxy, above groups are further optionallysubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈alkylthio, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, C₁₋₈ alkylsulfonyl, C₁₋₈ alkylsulfonylamino, amino,mono-C₁₋₈ alkylamino, di-C₁₋₈ alkylamino, ═O or hydroxyl;

R₁₃ and R₁₄ are each independently selected from the group consisting ofH, deuterium, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₈alkylsulfonyl and C₁₋₈ alkanoyl, or R₁₃ and R₁₄ are taken together withthe directly attached nitrogen atom to form a 4-10 memberedheterocyclyl,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₈ alkysulfonyl,C₁₋₈ alkylsulfonylamino, amino, mono-C-s alkylamino, di-C-s alkylamino,═O or hydroxyl;

m is 0 or 1;

n is 0, 1 or 2;

r is 0, 1 or 2;

provided that, when X₃ is —(CR₈)_(n)—, X₂ is —C(O)—, X₄ is C, X₅ isselected from the group consisting of —N(R₉)— N, O and S; when X₃ is—C(O)—, X₂ is —N(R₉)—, and Z is selected from the group consisting ofC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl and phenyl.

In a further preferred embodiment, in the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof, Z is selectedfrom the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene, C₂₋₄alkynylene, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl and5-8 membered heteroaryl, above groups are further optionally substitutedby one or more substituents selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄—,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₁₀ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₁,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₁ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₁₋₄ alkoxyC₁₋₄ alkyl, C₃₋₆ cycloalkyloxyC₁₋₄ alkyl, C₃₋₆ cycloalkylC₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, 3-8 memberedheterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl and C₁₋₄ alkanoyl;

R₂, R₃, R₄, R₅, R₆ and R₇ are each independently selected from the groupconsisting of H, deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₁₋₄ alkenyl. C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—S(O)(NR₉)R₁₀, —C₀₋₄—P(O)(R₁₀)₂, —C₀₋₄—O—R₁₁,—C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄,—C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, or R₂and R₄, R₃ and R₅, R₄ and R₆, R₅ and R₆ are taken together with thedirectly attached carbon atoms to form a C₅₋₈ cycloalkyl, 5-8 memberedheterocyclyl, 5-8 membered aryl or 5-8 membered heteroaryl,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁.

In a further preferred embodiment, in the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof, Z is selectedfrom the group consisting of C₁₋₂ alkylene and the following structures:

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido. C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁.

In a further preferred embodiment, in the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof, R₁ is selectedfrom the group consisting of H, deuterium, methyl, isopropyl,methoxyethyl, cyclopropyloxymethyl, cyclopropylmethyl, allyl,cyclopropyl and acetyl;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl, —C₀₋₄—O—R₁₁ and—C₀₋₄—NR₁₃R₁₄, or R₂ and R₄, R₃ and R₅ are taken together with thedirectly attached carbon atoms to form a C₅₋₈ cycloalkyl, 5-8 memberedheterocyclyl, 5-8 membered aryl or 5-8 membered heteroaryl, above groupsare further optionally substituted by one or more substituents selectedfrom the group consisting of deuterium, halogen, cyano, nitro, azido,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₆ is H or deuterium.

In a further preferred embodiment, in the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof, R₁ is selectedfrom the group consisting of H, deuterium, methyl and cyclopropylmethyl;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, F, Cl, methyl, isopropyl, allyl, ethynyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl,—C₀₋₄—O—R₁₁ and —C₀₋₄—NR₁₃R₁₄, or R₂ and R₄, R₃ and R₅ are takentogether with the directly attached carbon atoms to form a 5-8 memberedheterocyclyl, the heteroatom is O or N, the 5-8 membered heterocyclyl isoptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₆ is H or deuterium.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is the compoundof the following formula (IIa):

wherein X₃ is selected from the group consisting of —N(R₉)—, N, O and S;

Z is selected from the group consisting of C₁₋₂ alkylene and thefollowing structures:

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, F, Cl, methyl, isopropyl, allyl, ethynyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl,—C₀₋₄—O—R₁₁ and —C₀₋₄—NR₁₃R₁₄, or R₂ and R₄, R₃ and R₅ are takentogether with the directly attached carbon atoms to form a 5-8 memberedheterocyclyl, the heteroatom is O or N, the 5-8 membered heterocyclyl isoptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₇ is selected from the group consisting of H, deuterium, Cl, F,hydroxyl, allyl, ethynyl, cyclopropyl, 3-oxacyclobutyl, trifluoromethyl,trideuteromethyl, —C₀₋₄—O—R₁₁ and —C₀₋₄—NR₁₃R₁₄;

R₉ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₃₋₆ cycloalkyl and 3-8 membered heterocyclyl, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₁₋₄ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

X₁, X₂, X₅, R₈, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m, n, and r are as describedabove.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is selectedfrom the group consisting of the following compounds of formula(IIIa-1), (IIIa-2), (IIIa-3) and (IIIa-4):

wherein Z is selected from the group consisting of C₁₋₂ alkylene and thefollowing structures.

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium. Cl, F, hydroxyl, methyl, isopropyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl and—O—R₁₁, or R₂ and R₄, R₃ and R₅ are taken together with the directlyattached carbon atoms to form a 5-8 membered heterocyclyl, theheteroatom is N or O;

R₇ is selected from the group consisting of H, deuterium, Cl, F,hydroxyl, cyclopropyl and —O—R₁₁;

R₉ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₃₋₆ cycloalkyl and 3-8 membered heterocyclyl, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, —C₀₋₄—O—R₁₁, —C₀₋₄—NR₁₃R₁₄ and—C₀₋₄—C(O)NR₁₃R₁₄:

X₁, X₅, R₈, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m, n and r are described in claim1.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is selectedfrom the compound of the formula (IVa-1):

wherein X₅ is —CH— or N:Z is selected from the group consisting of C₁₋₂ alkylene and thefollowing structures:

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl. —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄. —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, Cl, F, hydroxyl, methyl, isopropyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl and—O—R₁₁, or R₂ and R₄, R₃ and R₅ are taken together with the directlyattached carbon atoms to form a 5-8 membered heterocyclyl, theheteroatom is N or O;

R₇ is selected from the group consisting of H, deuterium, Cl, F,hydroxyl, cyclopropyl and —O—R₁₁;

R₈ is selected from the group consisting of H, deuterium, halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10 memberedheteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—S(O)(NR₉)R₁₀, —C₀₋₈—P(O)(R₁₀)₂,—C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂,—C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and—C₀₋₈—N(R₁₃)—C(O)OR₁₁,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

X₁, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m, n and r are as described above.

In a further preferred embodiment, in the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof, R₈ is selectedfrom the group consisting of H, deuterium, halogen, cyano, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—O—R₁₁, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁,

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is selectedfrom the compound of the formula (IIb):

wherein X₃ is —(CR₈)_(n)— or —C(O)—;

Z is selected from the group consisting of C₁₋₂ alkylene and thefollowing structures:

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, F, Cl, methyl, isopropyl, allyl, ethynyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl,—C₀₋₄—O—R₁₁ and —C₀₋₄—NR₁₃R₁₄, or R₂ and R₄, R₃ and R₅ are takentogether with the directly attached carbon atoms to form a 5-8 memberedheterocyclyl, the heteroatom is N or O, the 5-8 membered heterocyclyloptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₇ is selected from the group consisting of H, deuterium, Cl, F,hydroxyl, allyl, ethynyl, cyclopropyl, 3-oxacyclobutyl, trifluoromethyl,trideuteromethyl, —C₀₋₄—O—R₁₁ and —C₀₋₄—NR₁₃R₁₄;

R₉ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₃₋₆ cycloalkyl and 3-8 membered heterocyclyl, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

X₁, X₂, X₅, R₈, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m, n and r are as describedabove;

provided that, when X₃ is —(CR₈)_(n)—, X₂ is —C(O)—, X₅ is —N(R₉)—, N, Oor S; when X₃ is —C(O)—, X₂ is —N(R₉)—, and Z is a C₁₋₄ alkyl or phenyl.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is selectedfrom the group consisting of the following compounds of the formula(IIIb-1) and (IIIb-2):

wherein Z is selected from the group consisting of C₁₋₂ alkylene and thefollowing structures

above groups are further optionally substituted by one or moresubstituents selected from the group consisting of deuterium, halogen,cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁;

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium Cl, F, hydroxyl, methyl, isopropyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl and—O—R₁₁, or R₂ and R₄, R₃ and R₅ are taken together with the directlyattached carbon atoms to form a 5-8 membered heterocyclyl, theheteroatom is N or O:

R₇ is selected from the group consisting of H, deuterium Cl, F hydroxyl,cyclopropyl and —O—R₁₁;

X₁, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m and r are as described above.

In a further preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof is selectedfrom the compound of formula (IIIb-3):

wherein R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, Cl, F hydroxyl, methyl, isopropyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl and—O—R₁₁, or R₂ and R₄, R₃ and R₅ are taken together with the directlyattached carbon atoms to form a 5-8 membered heterocyclyl, theheteroatom is N or O;

R₇ is selected from the group consisting of H, deuterium, Cl, F,hydroxyl, cyclopropyl and —O—R₁₁;

R₉ is selected from the group consisting of H, deuterium, C₁₋₄ alkyl,C₃₋₆ cycloalkyl or 3-8 membered heterocyclyl, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl 3-8 membered heterocycyl, —C₀₋₄—O—R₁₁, —C₀₋₄—NR₁₃R₁₄ and—C₀₋₄—C(O)NR₁₃R₁₄; X₁, R₈, R₁₀, R₁₁, R₁₃, R₁₄ and n are as describedabove.

In the most preferred embodiment, the compound of formula (I), thestereoisomer or pharmaceutically acceptable salt thereof includes, butis not limited to, the following compounds:

The second aspect of the invention provides a process for preparing theabove compound of formula (I), the stereoisomer or pharmaceuticallyacceptable salt thereof, which is carried out by the following wayaccording to the reaction steps of the allylamide group, when m=1:

or by the following way, when m=0:

optionally, a conversion reaction is further carried out between thedifferent substituents according to the different substituent;

wherein, X is a leaving group, and is preferably selected from the groupconsisting of Cl, Br, methylthio, methylsulfonyl and methoxy; R isselected from the group consisting of nitro, cyano and azido; Pg is anamino protecting group, and is preferably selected from the groupconsisting of tert-butyloxycarbonyl, benzyloxycarbonyl,2-biphenyl-2-propoxy carbonyl and p-toluenesulfonyl; and X₁, X₂, X₃, X₄,X₅, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, m, nand r are as described above.

In a further preferred embodiment, when X is methylsulfonyl, thecorresponding compound can be produced by an oxidation reaction of themethylthio when R is with an oxidizing agent such as m-CPBA(m-chloroperoxybenzoic acid).

In a further preferred embodiment, the conversion reaction between thedifferent substituents according to the different substituent meansthat, if necessary, the conversion of substituents can be carried out bythe conventional experiment in the art under the conditions meetingchemical synthesis principle according to the different definitions ofX₁, X₂, X₃, X₄, X₅, R₁, R₂, R₃, R₄, R₅, R₆, R⁷, R₈, R₉, R₁₀, R₁₁, R₁₂,R₁₃, and R₁₄, after the condensation reaction.

The third aspect of the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of the abovecompound of formula (I), stereoisomer or a pharmaceutically acceptablesalt thereof, and pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides use of the abovecompound of formula (I), the stereoisomer or pharmaceutically acceptablesalt thereof or the aforementioned pharmaceutical composition forpreparing a medicament as an FGFR4 inhibitor.

The fifth aspect of the present invention provides use of the abovecompound of formula (I), the stereoisomer or pharmaceutically acceptablesalt thereof or the aforementioned pharmaceutical composition forpreparing a medicament for treating cancer.

Preferably, the cancer is prostate cancer, liver cancer, pancreaticcancer, esophageal cancer, gastric cancer, lung cancer, breast cancer,ovarian cancer, colon cancer, skin cancer, glioblastoma orrhabdomyosarcoma.

The sixth aspect of the invention provides the above compound of formula(I), the stereoisomer or pharmaceutically acceptable salt thereof or theaforementioned pharmaceutical composition for use as an FGFR4 inhibitor.

The seventh aspect of the invention provides the above compound offormula (I), the stereoisomer or pharmaceutically acceptable saltthereof or the aforementioned pharmaceutical composition for use in thetreatment of cancer.

Preferably, the cancer is prostate cancer, liver cancer, pancreaticcancer, esophageal cancer, gastric cancer, lung cancer, breast cancer,ovarian cancer, colon cancer, skin cancer, glioblastoma orrhabdomyosarcoma.

The eighth aspect of the invention provides a method for inhibitingFGFR4, which comprises administering to a patient in need thereof atherapeutically effective amount of the above compound of formula (I),the stereoisomer or pharmaceutically acceptable salt thereof, or theaforementioned pharmaceutical composition.

The ninth aspect of the invention provides a method for treating cancer,which comprises administering to a patient in need thereof treatment atherapeutically effective amount of the above compound of formula (T),the stereoisomer or pharmaceutically acceptable salt thereof, or theaforementioned pharmaceutical composition.

Preferably, the cancer is prostate cancer, liver cancer, pancreaticcancer, esophageal cancer, gastric cancer, lung cancer, breast cancer,ovarian cancer, colon cancer, skin cancer, glioblastoma orrhabdomyosarcoma.

The series of compounds developed by the present invention have stronginhibitory effects on FGFR4 kinase activity and very high selectivity,and can be widely used for preparing a medicament for treating cancer,especially prostate cancer, liver cancer, pancreatic cancer, esophagealcancer, stomach cancer, lung cancer, breast cancer, ovarian cancer,colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma. Thecompounds are expected to be developed into a new generation medicamentsof FGFR4 inhibitor.

It is to be understood that within the scope of the present invention,the above various technical features of the present invention and thetechnical features specifically described hereinafter (as in theexamples) may be combined with each other to constitute a new orpreferred technical solution. Due to space limitations, they will not bedescribed one by one.

DETAILED DESCRIPTION OF THE INVENTION

Based on a long-term and in-depth study, the inventors have developedfor the first time an FGFR4 inhibitor with a structure of the formula(I), the series of compounds have very strong inhibitory effects onFGFR4 kinase activity and very high selectivity, and could be widelyused for preparing a medicament for treating cancer, especially prostatecancer, liver cancer, pancreatic cancer, esophageal cancer, stomachcancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skincancer, glioblastoma or rhabdomyosarcoma. These compounds will beexpected to be developed into a new generation medicaments of FGFR4inhibitor. On such basis, the present invention has been completed.

Detailed description: Unless otherwise stated, the following terms usedin the specification and claims have the following meanings.

“Alkyl” means a straight or branched saturated aliphatic hydrocarbongroup, for example, “C₁₋₈ alkyl” means a straight or branched alkylhaving 1 to 8 carbon atoms, including but is not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl,n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl,n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl,3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl,3-ethylhexyl 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl or various branched isomers thereof and so on.

Alkyl can be optionally substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, independently selected from the group consisting of deuteriumhalogen, cyano, nitro, azido C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl,5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Cycloalkyl” means a saturated or partially unsaturated monocyclic orpolycyclic hydrocarbon substituent, for example, “C₃₋₈ cycloalkyl”refers to a cycloalkyl having 3-8 carbon atoms, which may be amonocyclic cycloalkyl and a polycyclic cycloalkyl, wherein, monocycliccycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl,cycloheptyl, cycloheptatrienyl, cyclooctyl and the like; and polycycliccycloalkyl includes spiro, fused, and bridged cycloalkyls.

“Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom(called a spiro atom) between the monocyclic rings. These groups maycontain one or more double bonds, but none of the rings have a fullyconjugated π-electron system. The spirocycloalkyl may be amonospirocycloalkyl, a bispirocycloalkyl or a polyspirocycloalkylaccording to the number of common spiro atoms between the rings,spirocycloalkyl includes, but is not limited to:

“Fused cycloalkyl” means an all-carbon polycyclic group in which eachring shares an adjacent pair of carbon atoms with other rings in thesystem, wherein one or more of the rings may contain one or more doublebonds, but none of the rings have a fully conjugated π-electron system.Depending on the number of rings, it may be bicyclic, tricyclic,tetracyclic or polycyclic, fused cycloalkyl includes but is not limitedto:

“Bridged cycloalkyl” refers to an all-carbon polycyclic group in whichany two rings share two carbon atoms that are not directly bonded, whichmay contain one or more double bonds, but none of the rings have a fullyconjugated pi-electron system. Depending on the number of rings, it maybe bicyclic, tricyclic, tetracyclic or polycyclic, bridged cycloalkylincludes but is not limited to:

The ring of the cycloalkyl may be fused to a ring of aryl, heteroaryl orheterocycloalkyl, wherein the ring attached to the parent structure is acycloalkyl, includes, but is not limited to indanyl, tetrahydronaphthyl,benzocycloheptyl and the likes.

The cycloalkyl can be optionally substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Heterocyclyl” means a saturated or partially unsaturated monocyclic orpolycyclic cyclic hydrocarbon substituent wherein one or more of thering atoms are heteroatoms selected from nitrogen, oxygen or S(O),(wherein r is an integer of 0, 1, 2), but excluding ring moiety of—O—O—, —O—S— or —S—S—, and the remaining ring atoms are carbon atoms.For example, “5-10 membered heterocyclyl” means a cyclic groupcontaining 5 to 10 ring atoms, and “3-10 membered heterocyclyl” means acyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclyl includes, but is not limited to pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyland the likes.

Polycyclic heterocyclyl includes a spiro, fused, and bridgedheterocyclyl. “Spiroheterocyclyl” refers to a polycyclic heterocyclylthat shares a carbon atom (called a spiro atom) between the monocyclicrings, wherein one or more of the ring atoms are heteroatoms selectedfrom nitrogen, oxygen or S(O)_(r) (wherein r is an integer of 0, 1, 2),and the remaining ring atoms are carbon atoms. These groups may containone or more double bonds, but none of the rings have a fully conjugatedπ-electron system. The spiro heterocyclyl may be amonospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclylaccording to the number of common spiro atoms between the rings,spiroheterocyclyl includes, but is not limited to:

“Fused heterocyclyl” means a polycyclic heterocyclyl in which each ringshares an adjacent pair of carbon atoms with other rings in the system,wherein one or more of the rings may contain one or more double bonds,but none of the rings have a fully conjugated π-electron system, whereinone or more of the ring atoms are heteroatoms selected from nitrogen,oxygen or S(O)_(r) (wherein r is an integer of 0, 1, 2), and theremaining ring atoms are carbon atoms. Depending on the number of rings,it may be bicyclic, tricyclic, tetracyclic or polycyclic, fusedheterocyclyl includes, but is not limited to:

“Bridged heterocyclyl” refers to a polycyclic heterocyclyl in which anytwo rings share two carbon atoms that are not directly bonded, which maycontain one or more double bonds, but none of the rings have a fullyconjugated pi-electron system wherein one or more of the ring atoms areheteroatoms selected from nitrogen, oxygen or S(O)_(r) (wherein r is aninteger of 0, 1, 2), and the remaining ring atoms are carbon atoms.Depending on the number of rings, it may be bicyclic, tricyclic,tetracyclic or polycyclic, bridged heterocyclyl includes, but is notlimited to:

The ring of the heterocycyl may be fused to a ring of aryl heteroaryl orcycloalkyl wherein the ring attached to the parent structure is aheterocyclyl, includes but is not limited to:

The heterocycyl can be optionally substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Aryl” means an all-carbon monocyclic or fused polycyclic (ie, a ringthat shares a pair of adjacent carbon atoms) group, and a polycyclicgroup having a conjugated π-electron system (i.e., a ring with adjacentpairs of carbon atoms), for example, “C₅₋₁₀ aryl” means an all-carbonaryl having 5-10 carbons, and “5-10 membered aryl” means an all-carbonaryl having 5-10 carbons, including but not limited to phenyl andnaphthyl. The aryl ring may be fused to a ring of heteroaryl,heterocyclyl or cycloalkyl, wherein the ring attached to the parentstructure is an aryl ring, includes, but is not limited to:

The aryl group can be optionally substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, and independently selected from the group consisting of halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈haloalkyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Heteroaryl” refers to a heteroaromatic system containing 1 to 4heteroatoms including a hetero atom selected from nitrogen, oxygen orS(O)r (wherein r is an integer of 0, 1, 2), for example, 5-7 memberedheteroaryl refers to a heteroaromatic system containing 5 to 7 ringatoms, and 5-10 membered heteroaryl refers to a heteroaromatic systemcontaining 5 to 10 ring atoms, including but not limited to furyl,thiophenyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl,imidazolyl, tetrazolyl group or the like. The heteroaryl ring may befused to a ring of aryl, heterocyclyl or cycloalkyl wherein the ringattached to the parent structure is a heteroaryl ring, includes, but isnot limited to

The heteroaryl can be optionally substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Alkenyl” refers to an alkyl group as defined above consisting of atleast two carbon atoms and at least one carbon-carbon double bond, forexample, C₂₋₈ alkenyl refers to a straight or branched alkenylcontaining 2 to 8 carbons. Alkenyl includes, but is not limited tovinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the likes.

The alkenyl group can be substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₃,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Alkynyl” refers to an alkyl group as defined above consisting of atleast two carbon atoms and at least one carbon-carbon triple bond, forexample, C₂₋₈ alkynyl refers to a straight or branched alkynylcontaining 2 to 8 carbons. Alkynyl includes, but is not limited toethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the likes.

The alkynyl can be substituted or unsubstituted, and when substituted,the substituent is preferably one or more of the following groups, andindependently selected from the group consisting of deuterium halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄, —C₀₋₈—C(O)NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Alkoxy” means —O-(alkyl), wherein alkyl is as defined above, forexample, “C₁₋₈ alkoxy” refers to an alkyloxy containing 1 to 8 carbons.Alkoxy includes, but is not limited to methoxy, ethoxy, propoxy, butoxy,and the likes.

The alkoxy can be substituted or unsubstituted, and when substituted,the substituent is preferably one or more of the following groups, andindependently selected from the group consisting of deuterium halogen,cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁, —C₀₋₈—C(O)OR₁₁,—C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R¹⁴, —C₀₋₈—C(O)NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“Cycloalkyloxy” means —O-(unsubstituted cycloalkyl), wherein cycloalkylis as defined above, for example, “C₃₋₈ cycloalkyloxy” refers to acycloalkyoxy containing 3 to 8 carbon atoms. Cycloalkyloxy includes, butis not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and the likes.

The cycloalkyloxy can be substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocycyl-,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“3-10 membered heterocyclyloxy” means —O-(unsubstituted 3-10 memberedheterocyclyl), wherein 3-10 membered heterocyclyl is as defined above,3-10 membered heterocyclyloxy can be substituted or unsubstituted, andwhen substituted, the substituent is preferably one or more of thefollowing groups, and independently selected from the group consistingof deuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“C₅₋₁₀ aryloxy” means —O-(unsubstituted C₅₋₁₀ aryl), wherein C₅₋₁₀ arylis as defined above, C₅₋₁₀ aryloxy can be substituted or unsubstituted,and when substituted, the substituent is preferably one or more of thefollowing groups, and independently selected from the group consistingof deuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“5-10 membered heteroaryloxy” means —O-(unsubstituted 5-10 memberedheteroaryl), wherein 5-10 membered heteroaryl is as defined above, 5-10membered heteroaryloxy can be substituted or unsubstituted, and whensubstituted, the substituent is preferably one or more of the followinggroups, and independently selected from the group consisting ofdeuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁.

“C₁₋₈ alkanoyl” refers to a monovalent group obtained by removinghydroxyl from C-s alkyl acid, is also generally referred to as“C₀₋₇—C(O)—”, for example, “C₁—C(O)—” refers to acetyl; “C₂—C(O)—”refers to propionyl; and “C₃—C(O)—” refers to butyryl or isobutyryl.

“—C₀₋₈—S(O)_(r)R₁₀” means that the sulfur atom in —S(O)_(r)R₁₀ is bondedto C₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is asdefined above.

“—C₀₋₈—O—R₁₁” means that the oxygen atom in —O—R₁₁ is bonded to C₀₋₈alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is as definedabove.

“—C₀₋₈—C(O)OR₁₁” means that the carbonyl group in —C(O)OR₁₁ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is as definedabove.

“—C₀₋₈—C(O)R₁₂” means that the carbonyl group in —C(O)R₁₂ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is as definedabove.

“—C₀₋₈—O—C(O)R₁₂” means that the oxygen atom in —O—C(O)R₁₂ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C-s alkyl is as definedabove.

“—C₀₋₈—NR₁₃R₁₄” means that the nitrogen atom in —NR₁₃R₁₄ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is as definedabove.

“—C₀₋₈—C(O)NR₁₃R₁₄” means that the carbonyl in —C(O)NR₁₃R₁₄ is bonded toC₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkyl is as definedabove.

“—C₀₋₈—N(R₁₃)—C(O)R₁₂” means that the nitrogen atom in —N(R₁₃)—C(O)R₁₁is bonded to C₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkylis as defined above.

“—C₀₋₈—N(R₁₃)—C(O)OR₁₁” means that the nitrogen atom in —N(R₁₃)—C(O)OR₁₁is bonded to C₀₋₈ alkyl, wherein C₀ alkyl means a bond, and C₁₋₈ alkylis as defined above.

“C₁₋₈ haloalkyl” means a alkyl group having 1 to 8 carbon atoms, whereinany hydrogen atom on which is optionally substituted with F, Cl, Br orI, and includes, but is not limited to difluoromethyl, dichloromethyl,dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and thelikes.

“C₁₋₈ haloalkoxy” means an alkoxy having 1 to 8 carbon atoms, whereinany hydrogen atom on which is optionally substituted with F, Cl, Br orI, and includes, but is not limited to difluoromethoxy, dichloromethoxy,dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, andthe likes.

“Halogen” means F. Cl, Br or I. “THF” refers to tetrahydrofuran.“EA/EtOAc” refers to ethyl acetate. “MeOH” means methanol. “EtOH” refersto ethanol. “PivOH” refers to trimethylacetic acid. “DMSO” refers todimethyl sulfoxide. “DIMF” means N,N-dimethylformamide. “DIPEA” refersto diisopropylethylamine. “CH₃CN” means acetonitrile. “PE” meanspetroleum ether. “DCM/CH₂Cl₂” means dichloromethane. “DCE” refers todichloroethane. “DMA” refers to dimethylacetamide. “Et₃N” refers totriethylamine. “NH₄Cl” means ammonium chloride. “NMP” refers toN-methylpyrrolidone. “HOAc” refers to acetic acid. “TFA” refers totrifluoroacetic acid. “MeI” means methyl iodide. “K” means potassiumiodide. “MsC” refers to methylsulfonyl chloride. “SO₂Cl₂” means sulfonylchloride. “POCl₃” refers to phosphorus oxychloride. “MeONa” means sodiummethoxide. “NaHCO₃” refers to sodium bicarbonate. “Na₂SO₄” means sodiumsulfate. “K₂CO₃” means potassium carbonate. “NaN₃” refers to sodiumazide. “NaH” refers to sodium hydride. “CuI” refers to cuprous iodide.“PPA” refers to polyphosphoric acid. “m-CPBA” refers tom-chloroperoxybenzoic acid. “MnO₂” means manganese dioxide. “LiAlH₄”means lithium aluminum hydride. “LiOH” refers to lithium hydroxide.“NaOAc” refers to sodium acetate. “NaNO₂” refers to sodium nitrite.“AgNO₃” means silver nitrate. “Boc₂O” refers to di-tert-butyldicarbonate. “LiCl” means lithium chloride. “Zn(CN)₂” refers to zinccyanide. “IBX” means 2-iodoxybenzoic acid. “Pd/C” means palladiumcarbon. “Pd(OAc)₂” means palladium acetate. “PPh₃” meanstriphenylphosphine. “Pd(PPh₃)₂Cl₂” means palladiumbis(triphenylphosphine) dichloride. “Pd₂(dba)₃” meanstris(dibenzylideneacetone) dipalladium. “Pd(dppf)Cl₂” means[1,1′-bis(diphenylphosphino)ferrocene] palladium dichloride. “Pd(PPh₃)₄”means tetrakis (triphenylphosphine) palladium. “brett-phos” refers todicyclohexyl[3,6-dimethoxy-2′,4″-triisopropyl[1,1′-biphenyl]-2-yl]phosphine.

“Optional” or “optionally” means that the event or environmentsubsequently described may, but need not, occur, including where theevent or environment occurs or does not occur. For example,“heterocyclyl optionally substituted by alkyl” means that an alkyl groupmay be, but is not necessarily, present, and the description includesthe case where the heterocyclyl is substituted with an alkyl and thecase where the heterocyclyl is not substituted with an alkyl.

“Substituted” means that one or more hydrogen atoms in a group are eachindependently substituted with a corresponding number of substituents.It goes without saying that a substituent is only in its possiblechemical position, and those skilled in the art will be able todetermine (by experiment or theory) possible or impossible substitutionwithout undue efforts. For example, it may be unstable that an aminogroup or a hydroxyl group having a free hydrogen is attached with acarbon atom having an unsaturated bond (such as an olefin).

“Pharmaceutical composition” means a mixture comprising one or more ofthe compounds described herein, or a physiologically/pharmaceuticallyacceptable salt or pro-drug thereof, and other chemical components, forexample physiological/pharmaceutically acceptable carriers andexcipients. The purpose of the pharmaceutical composition is to promotethe administration to an organism, which facilitates the absorption ofthe active ingredient thereby exerting biological activities.

The Present Invention Will be Further Described in Detail Below inConjunction with the Embodiments which is not Intended to Limit thePresent Invention. The Present Invention is Also not Limited to theContents of the Embodiments.

The structure of the compound of the present invention is determined bynuclear magnetic resonance (NMR) or/and liquid chromatography-massspectrometry (LC-MS). The NMR chemical shift (δ) is given in parts permillion (ppm). The NMR is measured by a Bruker AVANCE-400 nuclearmagnetic apparatus, and the solvent is deuterated dimethyl sulfoxide(DMSO-d₆), deuterated methanol (CD₃OD) and deuterated chloroform(CDCl₃), and the internal standard is tetramethylsilane (TMS).

The measurement of LC-MS is performed by using an Agilent 6120 massspectrometer. The measurement of HPLC is performed by using an Agilent1200 DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mmcolumn) and a Waters 2695-2996 high pressure liquid chromatograph(Gimini C18 150×4.6 mm column).

The thin layer chromatography silica gel plate is Yantai Yellow SeaHSGF254 or Qingdao GF254 silica gel plate. The specification of TLC is0.15 mm-0.20 mm, and the specification for thin layer chromatographyseparation and purification is 0.4 mm-0.5 mm. 200-300 mesh silica gel(Yantai Huanghai silica gel) as a carrier is generally used in columnchromatography.

The starting materials in the examples of the present invention areknown and commercially available or can be synthesized according tomethods known in the art.

Unless otherwise stated, all reactions of the present invention arecarried out under continuous magnetic stirring under a dry nitrogen orargon atmosphere, the solvent is a dry solvent, and the unit of thereaction temperature is degrees Celsius.

Preparation of Intermediates Intermediate 1: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one

Step 1: Preparation of Ethyl 6-chloro-4-methoxynicotinate

Ethyl 4,6-dichloronicotinate (10.0 g, 45.4 mmol) was added to anhydrousTHF (100 mL), and cooled to 0° C. with ice water, then MeONa (2.8 g,51.8 mmol) was added. After the addition was completed, the mixture wasstirred at room temperature overnight. After the reaction as completed,the mixture was concentrated to remove THF. The crude product wasdissolved in ethyl acetate (100 mL), washed twice with water and driedover anhydrous Na₂SO₄ filtrated and concentrated to obtain ethyl6-chloro-4-methoxynicotinate (8.2 g, yield: 84%). MS (ESI): m/z 216.3[M+1]⁺.

Step 2: Preparation of (6-chloro-4-methoxypyridin-3-yl)methano

Ethyl 6-chloro-4-methoxynicotinate (8.2 g, 38.1 mmol) was dissolved inanhydrous THF (200 mL), then LiAH₄ (3.0, 81.1 mmol) was added underice-water bath. After the addition was completed, the mixture, wasstirred at room temperature for 2 h. After the reaction was completed,2N aqueous NaOH (25 mL) was added for extraction. The solid residue wasremoved by filtration, and the filtrate was concentrated to obtaincompound (6-chloro-4-methoxypyridin-3-yl)methanol (6.0 g, yield: 91%).MS (ESI): m/z 2174.2 [M+1]⁺.

Step 3: Preparation of 6-chloro-4-methoxynicotinaldehyde

(6-chloro-4-methoxypyridin-3-yl)methanol (6.0 g, 34.6 mmol) wasdissolved in acetone (100 mL), then IBX (12.0 g, 42.9 mmol) was added.The mixture was heated to reflux for 18 h. After the reaction wascompleted, the mixture was filtered and concentrated to obtain compound6-chloro-4-methoxynicotinaldehyde (4.2 g, yield: 71%). MS (ESI): m/z172.2 [M+1]⁺.

Step 4: Preparation of 6-chloro-4-hydroxyinicotinaldehyde

6-chloro-4-methoxynicotinaldehyde (4.2 g, 24.5 mmol) was dissolved in1,4-dioxane (30 ml), then concentrated hydrochloric acid (10 n) wasadded. The mixture was heated to 90° for 16 h. After the reaction wascompleted, the mixture was concentrated. The crude product was separatedby silica gel column chromatography to obtain compound6-chloro-4-hydroxylnicotinaldehyde (1.5 g, yield: 39%).

¹H NMR (400 MHz, CDCl₃): δ ppm 11.37 (s, 1H), 9.99 (s, 1H), 8.57 (s,1H), 6.99 (s, 1H).

Step 5: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one

6-chloro-4-hydroxylnicotinaldehyde (0.60 g, 3.82 mmol) was added toacetic anhydride (10 mL), then 2-(3,5-dimethoxyphenyl)acetic acid (0.80g, 4.08 mmol) and triethylamine (1.5 g, 107 mmol) were added, themixture was heated to 110° C. for 40 min. After the reaction wascompleted, the mixture was cooled to room temperature and concentrated.The obtained solids were washed with petroleum ether/ethyl acetate (3:1)to obtain compoundd7-chloro-3-(3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one (0.35 g,yield: 29%). MS (ESI): m/z 318.3 [M+1]⁺.

Step 6: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one

7-chloro-3-(3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one (0.35 g,1.1 mmol) was dissolved in anhydrous acetonitrile (10 mL), the mixturewas cooled to −30° C., then SO₂Cl₂ (1.0 g, 7.4 mmol) was added dropwise,the mixture was stirred at this temperature for 1 h. A saturated aqueoussolution of NaHCO₃ was added to quench the reaction, and thenacetonitrile was removed by concentration. After filtration, the solidswere washed with water and then petroleum ether/ethyl acetate (3:1) toobtain7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one(0.21 g, yield: 49%). MS (ESI): m/z 3863 [M+1]⁺.

Intermediate 2: Preparation of2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine

Step 1 Preparation of 2-Chloro-5-Nitroisonicotinic Acid

Chromium trioxide (40.0 g, 40 mmol) was added to a solution of2-chloro-4-methyl-5-nitropyridine (20.0 g, 11.6 mmol) in sulfuric acid(200 mL) at 0°. After the addition was completed, the mixture wasstirred at 0° C. for 1 h, then slowly warmed to room temperature andstirred overnight, and then poured into ice water (1 L) and filtrated toobtain 2-chloro-5-nitroisonicotinic acid (18 g, yield: 77%). MS (ESI):m/z 201.1 [M−1]⁻.

Step 2: Preparation of Methyl 2-Chloro-5-Nitroisonicotinate

Oxalyl chloride (12.7 g, 100 mmol) was added to a suspension of2-chloro-5-nitroisonicotinic acid (16 g, 80 mmol) in dichloromethane(150 mL) at 0°. After the addition was completed, the mixture wasstirred at room temperature for 3 h. Methanol (100 mL) was added, thereaction mixture was stirred at room temperature for another 4 h andthen concentrated. The crude product was dissolved in dichloromethane(200 ml), the mixture was washed with sodium bicarbonate solution (100mL*2), dried over anhydrous sodium sulfate and concentrated to obtainmethyl 2-chloro-5-nitroisonicotinate (17.2 g, yield: 98%).

Step 3: Preparation of Methyl2-(3,5-dimethoxyphenyl)-5-nitroisonicotinate

3,5-dimethoxyphenylboronic acid (8.47 g 46 mmol),tetrakis(triphenylphosphine)palladium (5 g, 4.6 mmol) and sodiumcarbonate (5 g 16 mmol) were added to a solution of methyl2-chloro-5-nitroisonicotinate (10.0 g, 46.0 mmol) in the mixture ofdioxane (200 mL) and water (50 mL). After the addition was completed,the mixture was stirred under N2 at 110° C. until the reaction of thestarting materials was completed. The reaction solution was concentratedand separated by column chromatography (eluent: CH₂Cl₂/PE 20:1) toobtain compound methyl 2-(3,5-dimethoxyphenyl)-5-nitroisonicotinate (6g, yield: 41%). MS (ESI): m/z 2318.9 [M+1]⁺.

Step 4: Preparation of Methyl5-amino-2-(3,5-dimethoxyphenyl)isonicotinate

Palladium carbon (10%, 500 mg) was added to a solution of methyl2-(3,5-dimethoxyphenyl)-5-nitroisonicotinate (6 g, 18.8 mmol) inmethanol (100 mL). Then the mixture was stirred under a hydrogenatmosphere at room temperature for 4 h, filtrated and concentrated toobtain methyl 5-amino-2-(3,5-dimethoxyphenyl)nitroisonicotinate (5 g,yield: 92.3%). MS (ESI): m/z 289.3[M+1]⁺.

Step 5: Preparation of6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione

A mixture of methyl 5-amino-2-(3,5-dimethoxyphenyl)isonicotinate (5 g,17.4 mmol) and urea (12 g, 200 mmol) was heated to 160° C. and stirredfor 4 h. Then the mixture was poured into ice water (100 mL) andfiltered to obtain6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (6 g,yield: 99%). MS (ESI): m/z 300.3 [M+1]⁺.

Step 6: Preparation of2,4-dichloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine

N,N-diethylaniline (3 mL) was added to a suspension of6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (5.0 g,16.7 mmol) in phosphorus oxychloride (50 m L). The mixture was thenstirred at 110° C. overnight. The solvent was evaporated, ice w ater(200 mL) was added, and pH was adjusted to 7 with aqueous sodiumbicarbonate solution. The aqueous solution was extracted for three timeswith EtOAc (50 mL). The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated and separated by column chromatography[eluent: (EA:PE=1:5)] to obtain compound2,4-dichloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine (2.5 g,yield: 44.5%). MS (ESI): m/z 336.2 [M+1]⁺.

Step 7: Preparation of2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine

A concentrated aqueous ammonia (2 g) was added to a solution of2,4-dichloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine (5 g, 7.5mmol) in methanol (100 mL). The mixture was then stirred at 25° C. for 4h. The pH was adjusted to 7 with hydrochloric acid (1N), then methanolis removed under vacuum,2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine (2 g,yield: 84%) was obtained after filtration. MS (ESI): m/z 317.1 [M+1]⁺.

Step 8: Preparation of2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine

Tert-butyl nitrite (720 mg, 6.2 mmol) was added to a solution of2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine (I g,3.1 mmol) in tetrahydrofuran (100 mL). The mixture was then heated toreflux and stirred for 48 h. The reaction mixture was concentrated andseparated by column chromatography [eluent: (EA:PE=1: 5-1:2)] to obtaincompound 2-chlor-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine (400 mg,yield: 41%).

¹H NMR (400 MHz, DMSO-d₆: δ 9.7 (s, 1H) 9.53 (s, 1H), 8.74 (s, 1H), 7.4(s, 2H), 6.64 (s, 1H), 3.88 (S, 61H);

MS (ESI): m/z 302.0 [M+1]⁺.

Step 9: Preparation of2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine

The compound was prepared referring to the synthesis method of step 6 ofintermediate 1.

Intermediate 3 and Intermediate 4: Preparation of2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine and2-chloro-6-(2-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine

2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine (120 mg, 0.4mmol) was dissolved in anhydrous acetonitrile (20 mL) then the mixturewas cooled to 0° C. with ice-water bath.1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (select-fluor, 283 mg, 0.8 mmol) was addeddropwise. After the addition was completed, the reaction solution waswarmed to room temperature for 6 h. The reaction was completed monitoredby TLC. A saturated aqueous NaHCO₃ solution was added to quench thereaction, and then majority of acetonitrile was removed. The mixture wasextracted with ethyl acetate, concentrated, and separated by silica gelcolumn chromatography (PE/EA=10/11, adjusted by adding 10% DCM) toobtain2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine(20mg, yield: 15%), MS m/z (ESI): 338 [M+H]+. At the same time,2-chloro-6-(2-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine(70 mg,yield:55%) was also obtained, MS m/z (ESI): 320 [M+H]⁺.

Intermediates 5-10 were prepared referring to the the synthesis methodof intermediate 2.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 5

2-chloro-6-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidine 355 6

2-chloro-6-(2-fluoro-6-isopropyl- 3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine 362 7

2-chloro-6-(2-cyclopropyl-6-fluoro- 3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine 360 8

2-chloro-6-(2-chloro-6-cyclopropyl- 3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine 377 9

2-chloro-6-(6-fluoro-7-methoxy-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)pyrido[3,4-d]pyrimidine 348 10

2-chloro-6-(6-chloro-7-methoxy-2,3- dihydrobenzo[b][1,4]dioxin-5-yl)pyrido[3,4-d]pyrimidine 365

Intermediate 11: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one

Step 1: Preparation of Methyl 5-bromo-2-chloroisonicotinate

5-bromo-2-chloroisonicotinic acid (30.0 g 12.6 mmol) was dissolved inmethanol (300 mL), then SOCl₂ (18.0 g, 15 mmol) was added, the mixturewas heated to 75° C. for 8 h. The reaction was completed monitored byLCMS. The mixture was cooled to room temperature and concentrated byreduced pressure, and then EtOAc (300 mL) was added to the residue. Themixture was washed with a saturated aqueous solution of NaHCO₃ driedover anhydrous Na₂SO₄, filtered and concentrated to obtain methyl5-bromo-2-chloroisonicotinate (32.0 g, yield: 99%). MS (ESI): m/z 251.9[M+1]⁺.

Step 2: Preparation of Methyl2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinate

Methyl 5-bromo-2-chloro isonicotinate 30 g, 120 mmol) was dissolved in1,4-dioxane (300 mL), and 3,5-dimethoxyphenylacetylene (20.4 g, 120mmol), CuI (2.28 g, 12 mmol), Pd(dppf)Cl₂ (4.2 g, 6 mmol) and Et₃N (12.0g, 120 mmol) were added, and the mixture was heated to 60° C. under N2for 6 h. The reaction was complete, and the mixture was filtered andconcentrated. The crude product was separated by silica gel columnchromatography (DCM:PE=20:1) to obtain compound methyl2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinate (22 g, yield:55%). MS (ESI): m/z 332.1 [M+1]⁺.

Step 3: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one

Methyl 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinate (21.0 g 63mmol) was added to PPA (200 mL), and the mixture was heated to 80° for 8h. The reaction was completed monitored by LCMS. The reaction mixturewas poured into ice water (1000 mL), and then filtered to obtain solidcompound 7-choro-3-(3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one(15.0 g, yield: 75%). MS (ESI): m/z 318.2 [M+1]⁺.

Step 4: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one

The compound was prepared referring to the synthetic method of step 6 ofIntermediate 1.

Intermediate 12: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one

Step 1: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-1(2H)-one

7-chloro-3-(3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one (15 g,47.3 mmol) was dissolved in DMF (200 mL), then concentrated aqueousammonia (150 mL) was added. The reaction mixture was heated to 80° C.for 48 h. The reaction was completed monitored by LCMS, and thenfiltered to obtain solid compound7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-1(2H)-one (7.5 g,yield: 50.5%).

¹H NMR (400 MHz, DMSO-d6): δ ppm 11.7 (m, 1H), 8.97 (s, 1-), 8.01 (s,1-), 7.14 (s, 1H), 6.97 (s, 21), 6.61 (s, 1H), 3.86 (s, 611).

MS (ESI): m/z 317.2 [M+1]⁺.

Step 2: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one

7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-(2H)-one (2 g, 6.32mmol) was dissolved in DMF (30 mL), and Na (758 mg, 18.95 mmol) wasadded under ice water bath. The mixture was stirred at 0° C. for 15minutes, then MeI (8,967 g, 63.151 mmol) was added dropwise, the mixturewas stirred at room temperature for 1 h. After the reaction wascompleted, it was quenched with water. The mixture was extracted forthree times with ethyl acetate, and the organic phases were combined andwashed with water, saturated brine, dried over anhydrous sodium sulfate,filtrated, concentrated and separated by column chromatography (Eluent:PE/EtOAc=2:1) to obtain compound7-chloro-3-(3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(1.35 g, yield: 65%).

MS m/z (ESI): 331.0 [M+H]⁺.

Step 3: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one

The compound was prepared referring to the synthetic method of step 6 ofIntermediate 1 MS m/z (ESI): 399.2 [M+H]⁺.

Intermediate 13-19 were prepared referring to the synthesis method ofIntermediate 12.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 13

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1(2H)-one 385 14

7-chloro-2-(cyclopropylmethyl)-3- (2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-1(2H)-one 440 15

N-(tert-butyl)-2-(7-chloro-3-(2,6- dichloro-3,5-dimethoxyphenyl)-1-oxo-2,6-naphthyridin-2(1H)- yl)acetamide 499 16

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(2-methoxyethyl)-2,6-naphthyridin- 1(2H)-one 444 17

2-chloro-6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-8(7H)-one 387 18

2-chloro-6-(2,6-dichloro-3,5- dimethoxyphenyl)-7-methylpyrido[3,4-d]pyrimidin- 8(7H)-one 401 19

2-chloro-7-(cyclopropylmethyl)-6- (2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-8(7H)-one 441

Intermediate 20: Preparation of6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4(3H)-one

Step-1: Preparation of 5-amino-2-chloroisonicotinamide

5-amino-2-chloroisonicotinic acid (4.0 g, 23 mmol) was added to SOCl₂(50 mL), the mixture was heated to 80° C. for 4 h. After the reactionwas completed, the mixture was cooled to room temperature andconcentrated. The residue was dissolved in anhydrous THF (20 mL), andthen the mixture was cooled under ice water bath, a concentrated aqueousammonia (100 mL) was added. The reaction was completed, and the mixturewas extracted for five times with CH₂Cl₂ (100 mL). The organic phaseswere combined, dried over anhydrous sodium sulfate, filtrated andconcentrated to obtain compound 5-amino-2-chloroisonicotinamide (3.5 gyield: 88%).

Step 2: Preparation of6-chloro-2-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4(3H)-one

5-amino-2-chloroisonicotinamide (3.5 g, 20.4 mmol) and3,5-dimethoxybenzaldehyde (3.7 g, 22.3 mmol) were dissolved in EtOH (50mL) then HOAc (10 mL) was added, the mixture was heated to 80° C. for 2days. The reaction liquid was concentrated, the residue was dissolved inthe mixture of CH₂Cl₂ (100 mL) and THF (100 mL). Then MnO₂ (17.0 g, 87.0mmol) was added, and the mixture was stirred at room temperature for 4days. The reaction was completed, the mixture was filtered andconcentrated. The residue was added to EtOAc (100 mL), stirred andfiltrated to obtain compound6-chloro-2-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (4.0 g,yield: 63%).

¹H NMR (400 MHz, DMSO-d6): δ ppm 12.78 (s, 1H), 8.91 (s, 1H), 7.95 (s,1H), 7.44 (s, 1H), 7.43 (s, 1H), 3.84 (s, 611).

Step 3: Preparation of6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4(3H)-one

6-chloro-2-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (1.0g, 3.2 mmol) was dissolved in CH₃CN (50 mL), then the mixture was cooledto −20° C., SO₂Cl₂ (0.85 g, 6.3 mmol) was added, the mixture was reactedat this temperature for 3 h. After the reaction was completed, asaturated aqueous solution of NaHCO₃ was added to quench the reaction,and the mixture was filtrated to obtain compound6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4(3H)-one(1.1 g, 92%). MS (ESI): m/z 386 [M+H]⁺.

Intermediate 21: Preparation of6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)-3-methylpyrido[3,4-d]pyrimidine-4(3H)-one

6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[34-d]pyrimidine-4(3H)-one(0.65 g, 1.68 mmol) was dissolved in DMF (20 mL), then the mixture wascooled to 0° under ice water bath, NaH (134 mg, 3.36 mmol) was added,the mixture was stirred at room temperature for 2 h. The reaction wascompleted, water (50 mL) was added to quench the reaction. The mixturewas filtrated, washed with water and dried to obtain compound6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one(0.65 g, yield:96%) MS n/z (ESI): 400 [M+H]⁺.

Intermediate 22: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

Step 1: Preparation of Ethyl6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinate

Ethyl 4,6-dichloronicotinate (4.0 g, 18.18 mmol) and trifluoroethylamine(2.7 g, 27.27 mmol) were dissolved in DMSO (50 mL) then Et₃N (5.5 g,54.55 mmol) was added, the mixture was heated to 120° C. for 12 h. Thereaction was completed, the mixture was cooled to room temperature,water (200 ml) was added, and then the mixture was extracted for threetimes with EtOAc (50 mL). The organic phase was dried over anhydroussodium sulfate, filtrated and concentrated. The crude product wasseparated by silica gel column chromatography (PE:EA=3:1) to obtaincompound ethyl 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinate (1.5g, yield: 29.1%). MS (ESI): m/z 283.0 [M+1]⁺.

Step 2: Preparation of(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol

Ethyl 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinate (1.5 g, 5.32mmol) was dissolved in dried T-IF (30 mL) then the mixture was cooledunder ice water bath LiAlH₄ (0.39 g, 10.64 mmol) was slowly added, andthe mixture was stirred at 0° C. for 2 h. The reaction was completed,Na₂SO₄.10H₂O was added to quench the reaction. The mixture wasfiltrated, and the filtrate was concentrated to obtain compound(6-chloro-4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)methanol (1.1 g,yield: 86%).

Step 3: Preparation of6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde

(6-chloro-4-((2,2-trifluoroethyl)amino)pyridin-3-yl)methanol (1.1 g,4.58 mmol) was dissolved in the mixture of CH₂Cl₂ and THF (30 mL/10 mL),then MnO₂ (4.78 g, 54.9 mmol) was added, and the mixture was stirred atroom temperature for 12 h. The reaction was completed, filtrated, andthe filtrate was concentrated to obtain crude product6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde (0.86, yield:79%).

Step 4: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

6-chloro-4-((2,2-trifluoroethyl)amino)nicotinaldehyde (0.86 g, 3.61mmol) was dissolved in DMF (20 mL), then methyl3,5-dimethoxyphenylacetate (760 mg, 3.61 mmol) and K₂CO₃ (1.5 g, 10.84mmol) were added, the mixture was heated to 110° C. for 3 h. After thereaction was completed, the mixture was concentrated and separated bysilica gel col un chromatography (PE:EA=10:1) to obtain7-chloro-3-(3,5-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one(960 mg, yield: 67%). MS (ESI): m/z 399.0 [M+1]⁺.

Step 5: Preparation of7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,6-naphthyridin-2(1H)-one

The compound was prepared referring to the synthetic method of step 6 ofIntermediate 1.

Intermediates 23-25 were prepared according to the synthesis method ofIntermediate 22.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 23

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin- 2(1H)-one 400 24

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-(tetrahydrofuran-3-yl)- 1,6-naphthyridin-2(1H)- one 456 25

7-chloro-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-1-(2-morpholinoethyl)-1,6- naphthyridin-2(1H)-one 499

Intermediate 26: Preparation of3-chloro-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine

Step 1: Preparation of 5-bromo-2-chloroisonicotinaldehyde

Diisopropylamine (8.95 g, 88 mmol) was dissolved in dried THF (100 mL)under N2, then the mixture was cooled to −78° C. N-butyllithium (50 ml,78 mmol) was added dropwise, and then the mixture was stirred at 0° C.for 10 min. The mixture was cooled to −78° C., then2-chloro-5-bromopyridine (10.0 g, 52 mmol) was added, the mixture wasstirred at −78° C. for 1 h then dried DMF (11.4 g, 0.16 mol) was addeddropwise, the mixture was stirred at this temperature for another 1 h. Aammonium chloride solution was added to quench the reaction, and themixture was diluted with EtOAc (300 mL), washed for three times withwater (50 mL), washed with saturated brine (100 mL), dried overanhydrous sodium sulfate, filtrated, concentrated and separated bycolumn chromatography (Eluent: PE/EtOAc 9:1) to obtain compound5-bromo-2-chloroisonicotinaldehyde (7.0 g, yield: 61%).

¹H NMR (400 MHz, CDCl3): δ 10.3 (s, 1H), 8.69 (s, 1H), 7.73 (s, 1H).

MS m/z (ESI): 252.0, 254.0, 256.0 [M+MeOH+H]⁺.

Step 2: Preparation of2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehyde

5-bromo-2-chloroisonicotinaldehyde (2.5 g, 11.3 mmol),1-ethynyl-3,5-dimethoxybenzene (1.93 g, 11.9 mmol), DIPEA (3.66 g, 28.4mmol), CuI (108 mg, 0.6 mmol) and Pd(PPh₃)₂Cl₂ (398 mg, 0.6 mmol) wereadded to 1,4-dioxane (50 mL) under N2, the mixture was heated to 50° C.for 1 h. After the reaction was completed, the mixture was diluted withEtOAc (300 mL), washed successively with water (50 mL×3) and saturatedbrine (100 mL), concentrated and separated by column chromatography(Eluent: PE/EtOAc 9:1) to obtain compound2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehyde (3.0 g,yield: 75%). MS m/z (ESI): 302.2, 3042 [M+H]⁺.

Step 3: Preparation of2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehydeoxime

2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehyde (0.6 g, 2mmol), NaOAc (245 mg, 3.0 mmol) and hydroxylamine hydrochloride (207 mg,3.0 mol) were dissolved in the mixture of ethanol and 1,2-dichloroethane(20 ml/1.2 mL) under N2, the mixture was heated to 50° C. for 50 min.After the reaction was completed, the mixture was diluted with EtOAc(200 mL) washed successively with water (50 mL×2) and saturated brine(80 mL), dried over anhydrous sodium sulfate, filtrated and concentratedto obtain compound2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehydeoxime (612mg, yield: 100%).

Step 4: Preparation of7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-2-oxide

2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehydeoxime (612mg, 1.9 mmol) and AgNO₃ (66 mg 0.38 mmol) were added to chloroform (20mL), the mixture was heated to 60° C. for 1 h. After the reaction wascompleted, the mixture was concentrated and separated by columnchromatography (Eluent: CH₂Cl₂/MeOH 35:1) to obtain compound7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-2-oxide (580 mg,yield: 95%).

MS m/z (ESI): 317.2, 319.2 [M+H]⁺.

Step 5: Preparation of3-chloro-7-(3,5-dimethoxyphenyl)-2,6-naphthyridine

7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-2-oxide (200 ng, 0.63mmol) was dissolved in dichloromethane (10 mL) tinder ice water bath,then phosphorus trichloride (0.7 mL, 1.4 mmol) was added, the mixturewas stirred at room temperature overnight. The reaction was completed,the mixture was washed successively with a saturated aqueous solution ofNaHCO₃ (20 ml), DCM (80 mL), saturated brine (50 ml), dried overanhydrous sodium sulfate, filtrated, concentrated and separated bycolumn chromatography (Eluent: CH₂Cl₂/MeOH 50:1) to obtain compound3-chloro-7-(3,5-dimethoxyphenyl)-2,6-naphthyridine (60 mg, yield: 32%).MS m/z (ESI): 301.1303.2 [M+H]+.

Step 6: Preparation of3-chloro-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine

The compound was prepared referring to the synthesis method ofIntermediate 1.

Intermediates 27-32 were prepared referring to the synthesis method ofIntermediate 26.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 27

3-chloro-7-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridine 337 28

3-chloro-7-(2-chloro-3,5- dimethoxyphenyl)-2,6-naphthyridine 336 29

3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)-2,6-naphthyridine354 30

3-chloro-7-(2-chloro-3,5-dimethoxy- 6-methylphenyl)-2,6-naphthyridine350 31

3-chloro-7-(2-chloro-6-isopropyl- 3,5-dimethoxyphenyl)-2,6-naphthyridine 378 32

3-chloro-7-(2-chloro-6-cyclopropyl- 3,5-dimethoxyphenyl)-2,6-naphthyridine 376

Intermediate 33: Preparation of7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine

Step 1: Preparation of7-chloro-1-((cyclopropylmethyl)amino)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine2-oxide

7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine 2-oxide (4.0 g, 12.6mmc) was dissolved in toluene (80 mL), cyclopropylmethylamine (7.19 g,0.1 mol) and CuI (241 mg, 1.26 mmol) were added successively, themixture was heated to 50 T overnight under an oxygen atmosphere. Afterthe reaction was completed, the reaction liquid was filtrated andconcentrated. The residue was separated by column chromatography(Eluent: dichloromethane/methanol 25:1) to obtain compound7-choro-1-((cyclopropylmethyl)amino)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine2-oxide (2.8 g, 57%).

MS m/z (ESI): 386.4 [M+H]⁺.

Step 2: Preparation of7-chloro-N-(cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine

7-chloro-1-((cyclopropylmethyl)amino)-3-(3,5-dimethoxyphenyl)-2,6-naphthridine2-oxide (2.8 g, 5.1 mmol) was dissolved in dichloromethane (40 mL), PCl₃(3 mL, 6.1 mmol) was added dropwise under ice water bath, the mixturewas stirred at room temperature for 1 h. A saturated solution of sodiumhydrogencarbonate (50 mL) was added, then the mixture was extracted withdichloromethane (100 mL×3), the organic phases were combined, dried overanhydrous sodium sulfate, concentrated and separated by columnchromatography (Eluent: dichloromethane/methanol 50:1) to obtaincompound7-chloro-N-(cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine(570 mg, 21%).

MS m/z (ESI): 370.4 [M+H]⁺.

Step 3: Preparation of7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine

7-chloro-N-(cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine(550 mg, 0.27 mmol) was added to acetonitrile (20 mL), then sulfonylchloride (73 mg, 0.54 mmol) was added dropwise at −30° C., the mixturewas stirred at this temperature for 1 h. A saturated solution of sodiumhydrogencarbonate (30 mL) was added, then the mixture was extracted withethyl acetate (50 mL×3), the organic phases were combined, dried overanhydrous sodium sulfate, filtrated, concentrated and separated bycolumn chromatography (Eluent: petroleum ether/ethyl acetate 10:1) toobtain compound 7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine(337 mg, 52%).

MS m/z (ESI+APCI): 438.2/440.2 [M+H]⁺.

Intermediates 34-131 were prepared referring to the synthesis method ofIntermediate 33.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 34

7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6- naphthyridine-1-amine 438 35

7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-di(methoxy-d₃)phenyl)-2,6- naphthyridine-1-amine 444 36

7-chloro-N-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-di(methoxy-d₃)phenyl)-2,6- naphthyridine-1-amine 412 37

7-chloro-N-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6- naphthyridine-1-amine 406 38

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-methoxyethyl)-2,6-naphthyridine-1-amine 442 39

2-((7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)amino)ethan-1-ol 428 40

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(isopropylthio)ethyl)-2,6-naphthyridine-1-amine 486 41

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(ethylsulfonyl)ethyl)-2,6-naphthyridine-1-amine 504 42

N¹-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-N²,N²-dimethylethane-1,2-diamine 455 43

N¹-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-N³,N³-dimethylpropane-1,3-diamine 469 44

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-methyl-2,6-naphthyridine-1-amine 398 45

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-ethyl-2,6-naphthyridine-1-amine 412 46

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2,2,2-trifluoroethyl)-2,6-naphthyridine-1- amine 466 47

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N,N-dimethyl-2,6-naphthyridine-1-amine 412 48

7-chloro-N-(cyclopropylmethyl)-3-(2,6- dichloro-3,5-dimethoxyphenyl)-N-methyl-2,6-naphthyridine-1-amine 452 49

N-(2-((7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-1- yl)amino)ethyl)methanesulfonamide505 50

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((tetrahydrofuran2-yl)methyl)-2,6-naphthyridine-1-amine 468 51

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((tetrahydrofuran-3-yl)methyl)-2,6-naphthyridine-1-amine 468 52

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(oxetan-3-ylmethyl)-2,6-naphthyridine-1-amine 454 53

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-naphthyridine- 1-amine 482 54

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(oxetan-3-yl)-2,6-naphthyridine-1-amine 440 55

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)-2,6-naphthyridine-1-amine 468 56

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(tetrahydrofuran-3-yl)-2,6-naphthyridine-1-amine 454 57

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-2,6- naphthyridine-1-amine 481 58

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-2,6- naphthyridine-1-amine 481 59

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-2,6- naphthyridine-1-amine 467 60

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylazetidin-3-yl)methyl)-2,6- naphthyridine-1-amine 467 61

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1-methylazetidin-3-yl)-2,6- naphthyridine-1-amine 453 62

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1-methylpiperidin-4-yl)-2,6- naphthyridine-1-amine 481 63

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylpiperidin-4-yl)methyl)- 2,6-naphthyridine-1-amine 495 64

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3-difluorocyclobutyl)-2,6- naphthyridine-1-amine 474 65

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3-difluorocyclopentyl)-2,6- naphthyridine-1-amine 488 66

7-chloro-N-(cyclopentylmethyl)-3- (2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine 466 67

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-phenethyl-2,6-naphthyridine-1-amine 488 68

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2,6- naphthyridine-1-amine 478 69

2-(4-(((7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-1- yl)amino)methyl)-1H-pyrazol-1-yl)ethan-1-ol 508 70

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-(2-methoxyethyl)-1H-pyrazol-4- yl)methyl)-2,6-naphthyridine-1-amine 522 71

N-benzyl-7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine- 1-amine 474 72

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)- 2,6-naphthyridine-1-amine 510 73

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-morpholinoethyl)-2,6-naphthyridine- 1-amine 497 74

2-((7-chloro-3-(2-chloro-3- methoxyphenyl)-2,6-naphthyridin-1-yl)amino)ethan-1-ol 364 75

2-((7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-1-yl)amino)ethan-1-ol 360 76

2-((7-chloro-3-(2-fluoro-3- methoxyphenyl)-2,6-naphthyridin-1-yl)amino)ethan-1-ol 348 77

N¹-(7-chloro-3-(2-chloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-N²,N²-dimethylethane-1,2-diamine 421 78

N¹-(7-chloro-3-(3,5-dimethoxyphenyl)- 2,6-naphthyridin-1-yl)-N²,N²-dimethylethane-1,2-diamine 387 79

N¹-(7-chloro-3-(2-fluoro-3- methoxyphenyl)-2,6-naphthyridin-1-yl)-N²,N²-dimethylethane-1,2-diamine 375 80

7-chloro-3-(2-fluoro-3,5- dimethoxyphenyl)-N-((tetrahydrofuran2-yl)methyl)- 2,6-naphthyridine-1-amine 418 81

7-chloro-3-(2-fluoro-3-methoxyphenyl)-N-((tetrahydrofuran2-yl)methyl)-2,6- naphthyridine-1-amine 388 82

(S)-7-chloro-N-(1-cyclopropylethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- 2,6-naphthyridine-1-amine 452 83

(S)-7-chloro-N-(1-cyclopropylethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6- naphthyridine-1-amine 420 84

7-chloro-N-cyclopropyl-3-(2,6-dichloro- 3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine 424 85

7-chloro-N-cyclopropyl-3-(2,6-difluoro- 3,5-dimethoxyphenyl)-2,6-naphthyridine-1-amine 392 86

1-(azetidin-1-yl)-7-chloro-3-(2,6- dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine 424 87

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-methoxyazetidin-1-yl)-2,6- naphthyridine 454 88

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3-methoxyazetidin-1-yl)- 2,6-naphthyridine 422 89

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-N,N- dimethylazetidin-3-amine 467 90

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-(trifluoromethyl)azetidin-1-yl)- 2,6-naphthyridine 492 91

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3,3-dimethylazetidin-1-yl)-2,6- naphthyridine 452 92

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3,3-difluoroazetidin-1-yl)-2,6- naphthyridine 460 93

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-3-methylazetidin-3-ol 454 94

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-methoxy-3-methylazetidin-1-yl)-2,6- naphthyridine 468 95

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3-methoxy-3-methylazetidin-1-yl)-2,6- naphthyridine 436 96

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-3-methylazetidin-3-carbonitrile 463 97

6-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2-oxa-6-azaspiro[3.3]heptane 466 98

6-(7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2-oxa-6-azaspiro[3.3]heptane 434 99

6-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-1-oxa-6-azaspiro[3.3]heptane 466 100

6-(7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-1-oxa-6-azaspiro[3.3]heptane 434 101

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(2-azaspiro[3.3]hept-2-yl)-2,6-naphthyridine 464 102

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(2-azaspiro[3.4]oct-2-yl)-2,6-naphthyridine 478 103

2-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-6-oxa-2-azaspiro[3.4]octane 480 104

2-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-7-oxa-2-azaspiro[3.5]nonane 494 105

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(pyrrolidin-1-yl)-2,6-naphthyridine 438 106

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-methoxypyrrolidin-1-yl)-2,6- naphthyridine 468 107

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3-methoxypyrrolidin-1-yl)-2,6- naphthyridine 436 108

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)pyrrolidine-3-carbonitrile 463 109

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3,3-difluoropyrrolidin-1-yl)-2,6- naphthyridine 474 110

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-methoxy-3-methylpyrrolidin-1-yl)-2,6- naphthyridine 482 111

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(3-methoxy-3-methylpyrrolidin-1-yl)-2,6- naphthyridine 450 112

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-3-methylpyrrolidine-3-carbonitrile 477 113

1-(3-azabicyclo[3.1.0]hex-3-yl)-7- chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine 450 114

7-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2-oxa-7-azaspiro[34.4]nonane 494 115

4-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)morpholine 454 116

4-(7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)morpholine 422 117

4-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2-methylmorpholine 468 118

4-(7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2-methylmorpholine 436 119

4-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2,6-dimethylmorpholine 482 120

4-(7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-2,6-dimethylmorpholine 450 121

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)piperidin-4-ol 468 122

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(4-methoxypiperidin-1-yl)-2,6- naphthyridine 482 123

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(4-methoxypiperidin-1-yl)-2,6- naphthyridine 450 124

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(3-methoxypiperidin-1-yl)-2,6- naphthyridine 482 125

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-4-methylpiperidin-4-ol 482 126

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-(4-methoxy-4-methylpiperidin-1-yl)-2,6- naphthyridine 496 127

7-chloro-3-(2,6-difluoro-3,5- dimethoxyphenyl)-1-(4-methoxy-4-methylpiperidin-1-yl)-2,6- naphthyridine 464 128

1-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)-4-methylpiperidine-4-carbonitrile 491 129

N-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)cyclopropyl carboxamide 452 130

N-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)tetrahydrofuran 2-carboxamide 482 131

N-(7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-1-yl)sulfonamide 462

Intermediate 132: Preparation of6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine

Step 1: Preparation of Methyl5-((3,5-dimethoxyphenyl)ethynyl)-2-methylthio)pyrimidine-4-carboxylate

Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (2631 mg, 10.0mmol) and 1-ethynyl-3,5-dimethoxybenzene (1622 mg, 10.0 mmol) weredissolved in dried THF (50 mL). The gas was exchanged with N₂, Et₃N (2.8mL, 20.0 mmol), Pd(PPh₃)₂Cl₂ (702 mg, 1.0 mmol), PPh₃ (525 mg, 2.0 mmol)and CuI (190 mg, 1.0 mmol) were added successively under N₂, the mixturewas heated to 90° C. and stirred overnight. After the reaction wascompleted, the mixture was cooled to room temperature, added with asaturated aqueous solution of NaHCO₃ (100 mL), extracted tice with EtOAc(100 mL), the organic phase was washed with saturated brine, dried overanhydrous sodium sulfate, filtrated, concentrated, and separated bysilica gel column chromatography (PE:EA 4:1) to obtain compound methyl5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate(2.5 g, yield: 73%). MS m/z (ESI): 345.2 [M+H]⁺.

Step 2: Preparation of5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylicAcid

Methyl5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate(600 m g, 1.742 mmol) was dissolved in methanol (15 mL), and then anaqueous lithium hydroxide monohydrate (366 mg, 8.711 mmol) in water (5mL) was added, and the mixture was stirred at room temperatureovernight. The reaction was completed. The organic solvent wasevaporated by reduced pressure, EtOAc (30 mL) was added to the residue,and the pH was adjusted with 1 N hydrochloric acid solution to 34. Theorganic phase was separated, washed with saturated brine, dried overanhydrous sodium sulfate, filtrated, and concentrated to obtain compound5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylicacid (584 mg, quantitative yield). MS m/z (ESI): 331.2 [M+H]+.

Step 3: Preparation of6-(3,5-dimethoxyphenyl)-2-(methylthio)-8H-pyrano[3,4-d]pyrimidine-8-one

5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylicacid (584 mg, 1.768 mmol) was suspended in acetone (25 mL), and AgNO₃(180 mg, 1.059 mmol) was added to the suspension. The mixture wasstirred at room temperature for 4 h, and green solid was precipitated,filtered to obtain6-(3,5-dimethoxyphenyl)-2-(methylthio)-8H-pyrano[3,4-d]pyrimidine-8-one(600 mg, the crude product) MS m/z (ESI): 331.2 [M+H]⁺.

Step 4: Preparation of6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one

6-(3,5-dimethoxyphenyl)-2-(methylthio)-8H-pyrano[3,4-d]pyrimidine-8-one(600 mg, the crude product) was added to glacial acetic acid (50 mL),then ammonium acetate (2.1 g, 27.243 mmol) was added, the mixture washeated to 115° C. for 16 h. The reaction was completed, the mixture wascooled to room temperature, poured slowly into a saturated aqueoussodium bicarbonate solution, and extracted with EtOAc (100 mL). Theorganic phase was separated, and washed with saturated brine, dried overanhydrous sodium sulfate, filtrated, concentrated and separated bycolumn chromatography (Eluent: CH₂Cl₂/MeOH 0˜6%) to obtain compound6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one(298 mg, two-step yield: 50%). MS m/z (ESI): 330.2 [M+H]⁺.

Step 5: Preparation of6-(3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine

6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one(100 mg, 0.304 mmol) and silver carbonate (109 mg, 0.395 mmol) weresuspended in toluene (3 mL), then methyl iodide (431 mg, 3.036 mmol) wasadded. The mixture was heated to 100° C. in a sealed tube for 3 h. Thereaction was completed, the mixture was cooled to room temperature,diluted with EtOA, and filtrated to remove salt. The filtrate wasconcentrated and separated by column chromatography (Eluent: PE/EtOAc10-80%) to obtain compound6-(3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine(47 mg, yield: 4 5%). MS m/z (ESI):344.3 [M+H]⁺.

Step 6: Preparation of6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine

The compound was prepared referring to the synthesis method ofIntermediate 1.

Intermediates 133-134 were prepared by referring, to the synthesismethod of example 1.2.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 133

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-ethoxy-2,6-naphthyridine 413 134

6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-ethoxy-2-(methylthio)pyrido[3,4- d]pyrimidine 426

Intermediate 135: Preparation of6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methoxyethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine

Step 1: Preparation of8-chloro-6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine

6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one(20.0 mg, 0.06 1 mmol) and N,N-diisopropylethylamine (78 mg, 0.610 mmol)were added to acetonitrile (2 mL), then POCl₃ (0.8 mL) was added, themixture was heated to 90° C. and stirred overnight. The solvent wasremoved by reduced pressure. The residue was diluted with EtOAc (10 mL)and washed with a saturated sodium bicarbonate solution. The organicphase was separated, washed with saturated brine, dried over anhydroussodium sulfate, filtrated, concentrated and separated by columnchromatography (Eluent: PE/EtOAc 040%) to obtain compound8-chloro-6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(6 mg, yield: 28%).

MS m/z (ESI): 348.2 [M+H]⁺.

Step 2: Preparation of6-(3,5-dimethoxyphenyl)-N-(2-methoxyethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine

8-chloro-6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(6 mg, 0.017 mmol) and N,N-diisopropylethylamine (6.5 mg, 0.052 mmol)were dissolved in acetonitrile (1.5 mL), then 2-methoxyethyl-1-amine (4mg, 0.052 mmol) was added, the mixture was heated to 90° C. and stirredovernight. The reaction was completed, the mixture was cooled to roomtemperature, diluted with EtOAc (5 mL), washed with saturated brine,dried over anhydrous sodium sulfate, filtrated, concentrated andseparated by column chromatography (Eluent: PE/EtOAc 0-50%) to obtaincompound6-(3,5-dimethoxyphenyl)-N-(2-methoxyethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine(4 mg, yield: 61%).

MS m/z (ESI): 387.4 [M+H]⁺.

Step 3: Preparation of6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methoxyethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine

The compound was prepared referring to the synthesis method ofIntermediate 1.

Intermediate 139: Preparation of4-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)morpholine

Step 1: Preparation of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene

2,6-difluoro-3,5-dimethoxyaniline (27.0 g, 143 mmol) was added to 6.0 Mhydrochloric acid solution (240 mL), and NaNO₂ aqueous solution (10.35g, 150 mmol, 30 mL water) was slowly added dropwise under ice water forcooling within 25 min. After the addition was completed, the mixture wasreacted for another 15 min to obtain an orange-re d suspension, and thenadded to an aqueous KI solution (94.9 g, 570 mmol, 150 mL water), themixture was heated to room temperature and stirred for 30 min toprecipitate a solid. The mixture was filtrated and washed with water toobtain a crude product. MeOH (60 mL) was added to the crude product,then the mixture was stirred at room temperature for 30 min, filtrated,and dried to obtain 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (29.3 g,yield: 68%).

Step 2: Preparation of(2,6-difluoro-3,5-dimethoxyphenylacetylene)trimethylsilane

2,4-difluoro-3-iodo-1,5-dimethoxybenzene (25.8 g, 86.0 mmol),trimethylsilylacetylene (36.5 mL, 258 mmol), CuI (817 mg, 4.3 mmol) andtriethylamine (35.8 mL, 258 mmol) were added to DMF (250 mL) under N2,then Pd(PPh₃)₂Cl₂ (3.15 g, 4.3 mmol) was added, and the mixture washeated to 50° C. for 2 h. The reaction was completed, a saturatedaqueous NH₄Cl solution was added to quench the reaction, the mixture wasextracted for three times with dichloromethane, and the organic phaseswere combined, dried over Na₂SO₄, filtrated and concentrated to obtain acrude product (27.0 g) which was used directly in the next step.

Step 3: Preparation of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene

(2,6-difluoro-3,5-dimethoxyphenylacetylene)trimethylsilane (27.0 g, acrude product) was added to the mixture of THF and MeOH (200/200 mL),then aqueous NaOH solution (8.6 mL, 8.6 mmol, 1.0 N) was added, and themixture was stirred at room temperature for 15 mm. The reaction wascompleted, a saturated aqueous NH₄Cl solution was added to quench thereaction, and the mixture was extracted for three times withdichloromethane, and the organic phases were combined, dried overanhydrous sodium sulfate, filtrated and concentrated. MeOH (50 mL) wasadded to the crude product, and then the mixture was stirred at roomtemperature for 30 min, filtered to obtain the target product (15.0 g,two-step yield: 88%).

Step 4: Preparation of Methyl5-((2,6-difluoro-3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate

3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (10.0 g, 50.5 mmol) andmethyl 5-bromo-2-methylthio-pyrimidine-4-carboxylate (13.0 g, 49.5 mmol)were dissolved in DMF (100 mL), then CuI (479 mg, 2.52 mmol), Pd(PPh₃)₄(2.91 g, 2.52 mmol) and Et₃N (35.0 mL, 252.5 mmol) were added, themixture was heated to 100° C. for 1.5 h under N2. The reaction wascompleted, the mixture was cooled to room temperature, a saturatedaqueous NH₄Cl solution was added to quench the reaction, then themixture was extracted for three times with dichloromethane, and theorganic phases were combined, dried over anhydrous sodium sulfate,filtrated and concentrated to obtain a crude product, then the crudeproduct was separated by silica gel column chromatography(PE:EA:DCM=10:2:1) to obtain the target product (15.4 g, yield: 82%). ¹HNMR (400 MHz, CDCl₃) δ 8.82 (s, 1H), 6.69 (t, J=8.0 Hz, 1H), 4.03 (s,3H), 3.90 (s, 6H), 2.63 (s, 3H).

Step 5: Preparation of5-((2,6-difluoro-3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylicAcid

Methyl5-((2,6-difluoro-3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate(30.0 g, 78.9 mmol) was dissolved in THF (300 mL), then LiOH/H₂O (236.8mL, 236.8 mmol, 1 M) was added, the mixture was stirred at roomtemperature for 2 h. The reaction was completed, the mixture wasconcentrated to remove THF, then acidified to pH 3 with dilutedhydrochloric acid to precipitate a solid. The mixture was filtrated,washed with water, and dried to obtain the target product (28.5 g,yield: 99%).

Step 6: Preparation of6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)-8H-pyrano[3,4-d]pyrimidine-8-one

5-((2,6-difluoro-3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylicacid (2.5 g, 6.83 mmol) was dissolved in DCE (50 mL), then TFA (0.5 mL)was added, the mixture was heated to reflux overnight. The reaction wascompleted, the mixture was concentrated, MeOH (50 mL) was added, thenthe mixture was stirred at room temperature for 30 min. The mixture wasfiltrated, and the solid was washed with MeOH (10 mL) to obtain thetarget product (2.0 g, yield: 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s,1H), 7.22 (t, J=8.4 Hz, 1H), 7.17 (s, 1H), 3.93 (s, 6H), 2.63 (s, 3H).

Step 7: Preparation of6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one

The compound was prepared referring to the synthesis method of step 4 ofIntermediate 132.

Step 8: Preparation of8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine

6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one(1 g, 2.74 mmol) was dissolved in DCE (80 mL), the mixture was heated to90° C., then phenylphosphonic dichloride (3.0 mL, 21.92 mmol) was added,the mixture was heated and stirred for 16 h, and then cooled. pH wasadjusted to neutral under ice bath. The mixture was extracted with DCM,and then separated by silica gel column chromatography (MeOH/DCM 1/20)to obtain compound8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(930 mg, yield:88%). MS m/z (ESI): 384 [M+H]⁺.

Step 9: Preparation ofN-(cyclopropylmethyl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine

The compound was prepared referring to the synthesis method of step 2 ofIntermediate 135.

Intermediates 136-330 were prepared referring to the synthesis method ofIntermediate 135 or 139.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 136

N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio) pyrido[3,4-d]pyrimidine-8-amine 451137

N-(cyclopropylmethyl)-6-(2,6-dichloro- 3,5-di(methoxy-d₃)phenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 457 138

N-(cyclopropylmethyl)-6-(2,6-difluoro- 3,5-di(methoxy-d₃)phenyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 425 140

2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)amino) ethan-1-ol 441 141

6-(2,6-dichloro-3,5-dimethoxyphenyl)- N-(2-(isopropylthio)ethyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 499 142

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(ethylsulfonyl)ethyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 518 143

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-methyl-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 411 144

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-ethyl-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 425 145

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N,N-dimethyl-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 425 146

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(2,2,2-trifluoroethyl)pyrido[3,4- d]pyrimidine-8-amine 479 147

N-(cyclopropylmethyl)-6-(2,6-dichloro- 3,5-dimethoxyphenyl)-N-methyl-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 465 148

N¹-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N²,N²- dimethylethane-1,2-diamine 468 149

N¹-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N³,N³- dimethylpropane-1,3-diamine 482 150

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)amino)ethyl)sulfonamide 518 151

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-((tetrahydrofuran2-yl)methyl) pyrido[3,4-d]pyrimidine-8-amine 481 152

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-((tetrahydrofuran-3-yl)methyl) pyrido[3,4-d]pyrimidine-8-amine 481 153

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(oxetan-3-ylmethyl)pyrido[3,4- d]pyrimidine-8-amine 467 154

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-((tetrahydro-2H-pyran-4-yl)methyl) pyrido[3,4-d]pyrimidine-8-amine 495155

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(oxetan-3-yl)pyrido[3,4-d]pyrimidine- 8-amine 453 156

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4- d]pyrimidine-8-amine 481 157

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(tetrahydrofuran-3-yl)pyrido[3,4- d]pyrimidine-8-amine 467 158

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 494 159

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)- 2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 494 160

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1- methylpyrrolidin-3-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 480 161

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methylazetidin-3-yl)methyl)- 2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 480 162

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1- methylazetidin-3-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 466 163

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(1- methylpiperidin-4-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 494 164

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1- methylpiperidin-4-yl)methyl)-2-(methylthio) pyrido[3,4-d]pyrimidine-8- amine 508 165

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3- difluorocyclobutyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 487 166

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3- difluorocyclopentyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 501 167

N-(cyclopentylmethyl)-6-(2,6- dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 479 168

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-phenethylpyrido[3,4- d]pyrimidine-8-amine 501 169

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-phenylpyrido[3,4- d]pyrimidine-8-amine 473 170

N-benzyl-6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 487 171

N-(3-aminobenzyl)-6-(2,6-dichloro- 3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 502 172

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2- (methylthio)pyrido[3,4- d]pyrimidine-8-amine491 173

2-(4-(((6-(2,6-dichloro-3,5- dimethoxyphenyl)-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)- 1H-pyrazol-1-yl)ethan-1-ol 521 174

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-(2-methoxyethyl)-1H-pyrazol-4- yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 535 175

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-neopentylpyrido[3,4-d]pyrimidine-8- amine 467 176

N¹-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N³- isopropylpropane-1,3-diamine 496 177

N¹-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N⁴- isopropylbutane-1,4-diamine 510 178

N¹-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N⁴,N⁴- dimethylbutane-1,4-diamine 496 179

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(4-(pyrrolidin-1-yl)butyl)pyrido[3,4- d]pyrimidine-8-amine 522 180

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 523 181

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-N-(2-morpholinoethyl)pyrido[3,4- d]pyrimidine-8-amine 510 182

N-(2-(3-aminopyrrolidin-1-yl)ethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 509 183

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl) ethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 537 184

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 512 185

(1-(4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)amino) butyl)pyrrolidin-2-yl)methanol 552186

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(4-(3,3-difluoropyrrolidin-1-yl)butyl)-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 558 187

6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(4-(3-methoxypyrrolidin-1-yl)butyl)-2- (methylthio)pyrido[3,4-d]pyrimidine-8-amine 552 188

N-(cyclopropylmethyl)-6-(2-fluoro- 3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 401 189

N-(cyclopropylmethyl)-6-(2-fluoro-3- methoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 371 190

6-(2-chloro-3-(methoxy-d₃)phenyl)-N- (cyclopropylmethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 390 191

N-(cyclopropylmethyl)-6-(2-fluoro-3- (methoxy-d₃)phenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 374 192

6-(2-chloro-3,5-di(methoxy-d₃) phenyl)-N-(cyclopropylmethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 423 193

N-(cyclopropylmethyl)-6-(2-fluoro- 3,5-di(methoxy-d₃)phenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 407 194

6-(2-chloro-3-methoxyphenyl)-2- (methylthio)-N-((tetrahydrofuran2-yl)methyl)pyrido[3,4-d]pyrimidine- 8-amine 417 195

6-(2-chloro-3-methoxyphenyl)-N-((1- methylpyrrolidin-2-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 430 196

6-(2-chloro-3,5-dimethoxyphenyl)- N-((1-methylpyrrolidin-2-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 460 197

6-(2-fluoro-3-methoxyphenyl)-N-((1- methylpyrrolidin-2-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 414 198

6-(2-chloro-3-methoxyphenyl)-N-(2- (4-methylpiperazin-1-yl)ethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 459 199

6-(2-chloro-3,5-dimethoxyphenyl)-N- (2-(4-methylpiperazin-1-yl)ethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 489 200

6-(2-chloro-3,5-dimethoxyphenyl)-2- (methylthio)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-8-amine 447 201

6-(3,5-dimethoxyphenyl)-N-(2-(4- methylpiperazin-1-yl)ethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 455 202

6-(2,6-difluoro-3,5-dimethoxyphenyl)- N-(2-methoxyethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 423 203

6-(2,6-difluoro-3,5-dimethoxyphenyl)- 2-(methylthio)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-8- amine 449 204

6-(2,6-difluoro-3,5-dimethoxyphenyl)- N-(1-methylpiperidin-4-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 462 205

6-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 491 206

6-(2,6-difluoro-3,5-dimethoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 462 207

6-(2,6-difluoro-3,5-dimethoxyphenyl)- N-(1-methylpyrrolidin-3-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 448 208

6-(2,6-difluoro-3,5-dimethoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 462 209

6-(2,6-difluoro-3,5-dimethoxyphenyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)- 2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 459 210

6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)-N-((tetrahydrofuran2-yl)methyl)pyrido[3,4-d]pyrimidine-8- amine 449 211

6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)-N-(tetrahydrofuran-3- yl)pyrido[3,4-d]pyrimidine-8-amine435 212

7-chloro-3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-isopropyoxy-2,6-naphthyridine 427 213

7-chloro-1-(cyclopropylmethoxy)-3- (2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine 439 214

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-isopropyoxy-2-(methylthio)pyrido[3,4-d]pyrimidine 440 215

8-(cyclopropylmethoxy)-6-(2,6- dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 452 216

(R)-N-(1-cyclopropylethyl)-6-(2,6- dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 465 217

(S)-N-(1-cyclopropylethyl)-6-(2,6- dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 465 218

(S)-6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3-dimethylbut-2-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 481 219

(R)-6-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3-dimethylbut-2-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 481 220

(R)-N-(1-cyclopropylethyl)-6-(2,6- difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 433 221

(S)-N-(1-cyclopropylethyl)-6-(2,6- difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine- 8-amine 433 222

(S)-6-(2,6-difluoro-3,5- dimethoxyphenyl)-N-(3,3-dimethylbut-2-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 449 223

(R)-6-(2,6-difluoro-3,5- dimethoxyphenyl)-N-(3,3-dimethylbut-2-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine-8-amine 449 224

N-cyclopropyl-6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 437 225

N-cyclopropyl-6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine 405 226

8-(azetidin-1-yl)-6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 437 227

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3-methoxyazetidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 467 228

6-(2,6-difluoro-3,5-dimethoxyphenyl)- 8-(3-methoxyazetidin-1-yl)-2-(methylsulfanyl)pyrido[3,4- d]pyrimidine 435 229

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-N,N- dimethylazetidin-3-amine 480 230

6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)-8-(3-(trifluoromethyl)azetidin-1- yl)pyrido[3,4-d]pyrimidine 505 231

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3,3-dimethylazetidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 465 232

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3,3-difluoroazetidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 473 233

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-3- methylazetidin-3-ol 467 234

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 481 235

6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 449 236

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-3- methylazetidin-3-carbonitrile 476 237

6-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa- 6-azaspiro[3.3]heptane 479 238

6-(6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa- 6-azaspiro[3.3]heptane 447 239

6-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-1-oxa- 6-azaspiro[3.3]heptane 479 240

6-(6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-1-oxa- 6-azaspiro[3.3]heptane 447 241

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(2-azaspiro[3.3]hept- 2-yl)pyrido[3,4-d]pyrimidine 477242

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(2-azaspiro[3.4]oct- 2-yl)pyrido[3,4-d]pyrimidine 491243

2-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-6-oxa- 2-azaspiro[3.4]octane 493 244

2-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-7-oxa- 2-azaspiro[3.5]nonane 507 245

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 2-(methylthio)-8-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine 451 246

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3-methoxypyrrolidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 481 247

6-(2,6-difluoro-3,5-dimethoxyphenyl)- 8-(3-methoxypyrrolidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 449 248

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl) pyrrolidine-3-carbonitrile 476 249

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3,3-difluoropyrrolidin-1-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 487 250

6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-(3-methoxy-3-methylpyrrolidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 495 251

6-(2,6-difluoro-3,5-dimethoxyphenyl)- 8-(3-methoxy-3-methylpyrrolidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 463 252

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-3- methylpyrrolidine-3-carbonitrile 490 253

8-(3-azabicyclo[3.1.0]hex-3-yl)-6- (2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 463 254

7-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa- 7-azaspiro[34.4]nonane 507 255

4-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl) morpholine 467 256

4-(6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl) morpholine 435 257

4-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylsulfanyl)pyrido[3,4-d]pyrimidin-8-yl)-2- methylmorpholine 481 258

4-(6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2- methylmorpholine 449 259

4-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2,6- dimethylmorpholine 495 260

4-(6-(2,6-difluoro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2,6- dimethylmorpholine 463 261

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)piperidin-4-ol 481 262

6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4- methoxypiperidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 495 263

6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(4- methoxypiperidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 463 264

6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3- methoxypiperidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 495 265

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-yl)-4- methylpiperidin-4-ol 495 266

6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4- methoxy-4-methylpiperidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 509 267

6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(4- methoxy-4-methylpiperidin-1-yl)-2-(methylthio)pyrido[3,4- d]pyrimidine 477 268

1-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)-4- methylpiperidine-4- carbonitrile 504 269

N-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)cyclopropyl carboxamide 465 270

N-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2- (methylthio)pyrido[3,4-d]pyrimidin-8-yl)tetrahydrofuran2- carboxamide 495 271

N-(6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)sulfonamide 475 272

6-chloro-N-(cyclopropylmethyl)-2- (2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine 439 273

6-chloro-N-(cyclopropylmethyl)-2- (2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine 407 274

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(2-methoxyethyl)pyrido[3,4-d]pyrimidine-4-amine 443 275

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-4-amine 455 276

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyrimidine- 4-amine 469 277

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine- 4-amine 469 278

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-(3,3-difluorocyclopentyl)pyrido[3,4- d]pyrimidine-4-amine 489 279

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-neopentylpyrido[3,4-d]pyrimidine- 4-amine 455 280

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)pyrido[3,4- d]pyrimidine-4-amine 479 281

(S)-6-chloro-N-(1-cyclopropylethyl)-2-(2,6-dichloro-3,5-dimethoxyphenyl) pyrido[3,4-d]pyrimidine-4-amine 453282

(S)-6-chloro-N-(1-cyclopropylethyl)-2-(2,6-difluoro-3,5-dimethoxyphenyl) pyrido[3,4-d]pyrimidine-4-amine 421283

6-chloro-N-cyclopropyl-2-(2,6- dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine 425 284

6-chloro-N-cyclopropyl-2-(2,6- difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-4-amine 393 285

4-(azetidin-1-yl)-6-chloro-2-(2,6- dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine 425 286

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-methoxyazetidin-1-yl)pyrido[3,4- d]pyrimidine 455 287

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(3-methoxyazetidin-1-yl)pyrido[3,4- d]pyrimidine 423 288

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-N,N- dimethylazetidin-3-amine 468 289

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-(trifluoromethyl)azetidin-1- yl)pyrido[3,4-d]pyrimidine 493 290

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3,3-dimethylazetidin-1-yl)pyrido[3,4- d]pyrimidine 453 291

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)pyrido[3,4- d]pyrimidine 461 292

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-3-methylazetidin- 3-ol 455 293

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4- d]pyrimidine 469 294

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4- d]pyrimidine 437 295

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-3-methylazetidin- 3-carbonitrile 464 296

6-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2-oxa-6- azaspiro[3.3]heptane 467 297

6-(6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2-oxa-6- azaspiro[3.3]heptane 435 298

6-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-1-oxa-6- azaspiro[3.3]heptane 467 299

6-(6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-1-oxa-6- azaspiro[3.3]heptane 435 300

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(2-azaspiro[3.3]hept-2-yl)pyrido[3,4-d]pyrimidine 465 301

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(2-azaspiro[3.4]oct-2-yl)pyrido[3,4- d]pyrimidine 479 302

2-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-6-oxa-2- azaspiro[3.4]octane 481 303

2-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-7-oxa-2- azaspiro[3.5]nonane 495 304

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine 439 305

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-methoxypyrrolidin-1- yl)pyrido[3,4-d]pyrimidine 469 306

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(3-methoxypyrrolidin-1-yl)pyrido[3,4- d]pyrimidine 437 307

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)pyrrolidine-3- carbonitrile 464 308

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)pyrido[3,4- d]pyrimidine 475 309

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-methoxy-3-methylpyrrolidin-1-yl) pyrido[3,4-d]pyrimidine 483 310

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(3-methoxy-3-methylpyrrolidin-1-yl)pyrido[3,4- d]pyrimidine 451 311

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-3-methylpyrrolidine- 3-carbonitrile 478 312

4-(3-azabicyclo[3.1.0]hex-3-yl)- 6-chloro-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4- d]pyrimidine 451 313

7-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2-oxa-7- azaspiro[4.4]nonane 495 314

4-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)morpholine 455 315

4-(6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)morpholine 423 316

4-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2-methylmorpholine 469 317

4-(6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2-methylmorpholine 437 318

4-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2,6- dimethylmorpholine 483 319

4-(6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-2,6- dimethylmorpholine 451 320

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)piperidin-4-ol 469 321

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(4-methoxypiperidin-1-yl)pyrido[3,4- d]pyrimidine 483 322

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(4-methoxypiperidin-1-yl)pyrido[3,4- d]pyrimidine 451 323

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(3-methoxypiperidin-1-yl)pyrido[3,4- d]pyrimidine 483 324

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-4-methylpiperidin- 4-ol 483 325

6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)pyrido[3,4- d]pyrimidine 497 326

6-chloro-2-(2,6-difluoro-3,5- dimethoxyphenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)pyrido[3,4- d]pyrimidine 465 327

1-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)-4-methylpiperidine- 4-carbonitrile 492 328

N-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)cyclopropyl carboxamide 453 329

N-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)tetrahydrofuran2- carboxamide 483 330

N-(6-chloro-2-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)sulfonamide 463

Intermediate 331: Preparation of8-cyclopropyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine

Step 1: Preparation of8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine

8-chloro-6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(500 mg, 1.43 mmol) was added to dichloromethane (30 mL), then themixture was cooled to −30° C. SO₂Cl₂ (0.35 mL, 4.31 mmol) was dissolvedin dichloromethane (30 mL), and slowly added dropwise to the abovereaction liquid with stirring. After the addition, the mixture wasstirred for another 0.5 h. The reaction was completed, then quenchedwith a saturated aqueous sodium bicarbonate solution (50 mL). Themixture was extracted, washed with water and then saturated brine, driedover anhydrous sodium sulfate, filtrated, concentrated and separated bycolumn chromatography to obtain8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(620 mg, 88%). MS m/z (ESI): 416.2 [M+H]⁺.

Step 2: Preparation of8-cyclopropyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine

8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(83 mg, 0.20 mmol), cyclopropyl boronic acid (26 mg, 0.30 mmol),Pd(OAc)₂ (5 mg, 0.02 m mol), PCy₃ (11 mg, 0.04 mmol) and K₃PO₄ (127 mg,0.60 mmol) were added to the mixture of toluene and water (6:1, 5 mL),the mixture was heated to 100° C. and stirred over night. The reactionwas completed, then the mixture was cooled to room temperature, dilutedwith EtOAc, washed with saturated brine, dried over anhydrous sodiumsulfate, filtrated, concentrated and separated by column chromatographyto obtain8-cyclopropyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(60 mg, 71%). MS m/z (ESI): 422.2 [M+H]⁺.

Intermediates 332-364 were prepared referring to the synthesis method of331.

Intermediate MS: m/z No. Compound structure Compound name [M + 1]⁺ 332

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[3,4-d] pyrimidine 396 333

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-2-(methylthio)pyrido[3,4-d] pyrimidine 410 334

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-isopropyl-2-(methylthio)pyrido[3,4-d] pyrimidine 424 335

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-neopentylpyrido[3,4-d] pyrimidine 452 336

8-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio) pyrido[3,4-d]pyrimidine 436 337

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-((tetrahydrofuran-3-yl) methyl)pyrido[3,4-d]pyrimidine466 338

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-((tetrahydrofuran2-yl) methyl)pyrido[3,4-d]pyrimidine 466339

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(tetrahydro-2H-pyran-4-yl) pyrido[3,4-d]pyrimidine 466340

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((1-methylpyrrolidin-3-yl)methyl)-2- (methylthio)pyrido[3,4-d]pyrimidine479 341

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((1-methylpyrrolidin-2-yl)methyl)-2- (methylthio)pyrido[3,4-d]pyrimidine479 342

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-methylpiperidin-4-yl)-2-(methylthio) pyrido[3,4-d]pyrimidine 479 343

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(2-methoxyethyl)-2-(methylthio)pyrido [3,4-d]pyrimidine 440 344

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methoxymethyl)-2-(methylthio)pyrido [3,4-d]pyrimidine 426 345

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)methyl)cyclopropylamine 451346

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)methyl)sulfonamide 489 347

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8- yl)methyl)propane-2-sulfonamide517 348

N-(2-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin- 8-yl)ethyl)propane-2-amine 467 349

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(2,2,2-trifluoroethyl)pyrido [3,4-d]pyrimidine 464 350

8-benzyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 472 351

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-phenylpyrido[3,4-d]pyrimidine 458 352

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(pyridin-4-yl)pyrido[3,4-d] pyrimidine 459 353

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(pyridin-3-yl)pyrido[3,4-d] pyrimidine 459 354

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio) pyrido[3,4-d]pyrimidine 462355

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((1-methyl-1H-pyrazol-4-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 476 356

8-(1-cyclopropyl-1H-pyrazol-4-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2- (methylthio)pyrido[3,4-d]pyrimidine 488357

8-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 502 358

6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2- (methylthio)pyrido[3,4-d]pyrimidine506 359

2-(4-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin- 8-yl)-1H-pyrazol-1-yl)ethan-1-ol492 360

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine 518 361

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-phenethylpyrido[3,4-d] pyrimidine 486 362

6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio) pyrido[3,4-d]pyrimidine 430363

6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine 474 364

2-(4-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin- 8-yl)-1H-pyrazol-1-yl)ethan-1-ol460

Intermediate 365: Preparation of(3S,4S)-4-azidotetrahydro-2H-pyran-3-amine Hydrochloride

Step 1: Preparation of Tert-Butyl((3S,4S)-4-hydroxyltetrahydro-2H-pyran-3-yl)carbamate

(3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (5.00 g, 42.7 mmol) wasdissolved in MeOH (100 mL), and then Et₃N (4.75 g, 47.0 mmol) and Boc₂O(10.25 g, 47.0 mmol) were successively added, the mixture was stirred atroom temperature overnight. The reaction was completed monitored byLCMS. The mixture was concentrated to remove methanol, and the crudeproduct was washed with petroleum ether (100 mL), and then filtrated toobtain tert-butyl ((3S,4S)-4-hydroxyltetrahydro-2H-pyran-3-yl)carbamate(8.50 g, yield: 92%).

¹H NMR (400 MHz, CDCl₃): δ ppm 4.68 (m, 1H), 4.03 (m, 1H), 3.93 (m, 1H),3.63 (m, 1H), 3.45 (m, 2H), 3.19 (m, 1H), 2.81 (m, 1H), 2.04 (m, 1H),1.68 (m, 1H), 1.61 (s, 9H).

Step 2: Preparation of(3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-ylMethanesulfonate

Tert-butyl ((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (8.5 g,39.2 mmol) was dissolved in CH₂Cl₂ (100 ML), the mixture was cooledunder ice water bath, and then Et₃N (4.30 g, 43.0 mmol) and MsCl (4.98g, 43.0 mmol) were successively added, the mixture was stirred at 0° C.for 6 h. The reaction was completed, the mixture was washed with water(20 mL), then the organic phase was dried over anhydrous sodium sulfate,filtrated, and concentrated to obtain(3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-ylmethanesulfonate (10.2 g, yield: 88%).

¹H NMR (400 MHz, CDCl₃): δ ppm 4.90 (m, 1H), 4.76 (m, 1H), 4.03 (m, 1H),3.98 (m, 1H), 3.67 (m, 2H), 3.47 (m, 1H), 3.14 (s, 3H), 2.18 (m, 1H),1.92 (m, 1H), 1.44 (s, 9H).

Step 3: Preparation of Tert-butyl((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate

(3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-ylmethanesulfonate (10.2 g, 34.6 mmol) was dissolved in dried DMF (100mL), NaOAc (9.38 g, 69.0 mmol) and NaN₃ (4.49 g, 69.0 mmol) weresuccessively added, the mixture was heated at 90° C. overnight. Thereaction was completed, then the reaction solution was poured into water(200 mL) and extracted twice with EtOAc (50 mL), the organic phases werecombined, washed twice with aqueous LiCl solution (50 mL), dried overanhydrous sodium sulfate, filtrated and concentrated to obtain compoundtert-butyl ((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (6.8 g,yield: 81%).

¹H NMR (400 MHz, CDCl₃): δ ppm 4.85 (m, 1H), 3.89 (m, 2H), 3.77 (m, 1H),3.63 (m, 2H), 3.51 (m, 1H), 1.93 (m, 2H), 1.45 (s, 9H).

Step 4: Preparation of (3S,4S)-4-azidotetrahydro-2H-pyran-3-amineHydrochloride

Tert-butyl ((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (6.8 g,28.0 mmol) was added to the mixture of HCl and EtOAc (100 mL), themixture was stirred at room temperature for 8 h. The reaction wascompleted monitored by LCMS. The mixture was concentrated to obtaincompound (3S,4S)-4-azidotetrahydro-2H-pyran-3-amine hydrochloride (4.0g, yield: 80%).

¹H NMR (400 MHz, DMSO-d6): δ ppm 8.47 (m, 3H), 4.36 (m, 1H), 3.80 (m,2H), 3.63 (m, 3H), 2.0 (m, 2H).

Intermediate 366: Preparation of (3S,4R)-4-azidotetrahydrofuran-3-amineHydrochloride

Intermediate 366 was prepared referring to the synthesis method ofIntermediate 365 from (3S,4R)-4-aminotetrahydro furan-3-ol.

Intermediate 367: Preparation of Tert-Butyl((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate

Step 1: Preparation of Tert-Butyl((3S,4R)-4-hydroxyltetrahydrofuran-3-yl)carbamate

(3R,4S)-4-aminotetrahydrofuran-3-ol (5.00 g, 48.487 mmol) was dissolvedin methanol (100 mL), then triethylamine (12.24 g, 121.2 mmol) wasadded, the mixture was cooled under ice water bath, then Boc₂O (11.64 g,53.34 mmol) was added. After the addition, the mixture was stirred atroom temperature for 24 h. The reaction was completed, the organic phasewas concentrated to remove the majority solvent. Water (100 mL) wasadded, and the mixture was stirred to precipitate a large amount ofwhite solids. The mixture was filtrated and washed with water to obtaincompound tert-butyl ((3S,4R)-4-hydroxyltetrahydrofuran-3-yl)carbamate(8.00 g, yield: 81%).

¹H NMR (400 MHz, Chloroform-d) δ 4.72 (s, 1H), 4.29 (m, 1H), 4.09 (m,1H), 4.08-4.02 (m, 1H), 3.95 (s, 1H), 3.69 (m, 1H), 3.61 (m, 1H), 1.45(s, 9H).

Step 2: Preparation of Tert-Butyl((3R,4S)-4-(1,3-dicarbonylisoindolin-2-yl)tetrahydrofuran-3-yl)carbamate

Tert-butyl ((3S,4R)-4-hydroxyltetrahydrofuran-3-yl)carbamate (200 mg,0.984 mmol), triphenylphosphine (620 mg, 2.364 mmol) andisoindoline-1,3-dione (173 mg, 1.181 mmol) were dissolved intetrahydrofuran (10 mL), the mixture was cooled under ice water bath,then diisopropyl azodicarboxylate (717 mg, 3.546 mmol) was slowly addeddropwise. After addition, the mixture was stirred under ice water bathfor 1 h. The reaction liquid was directly concentrated and separated bycolumn chromatography (Eluent: PE/EA 15-30%) to obtain a crude productcompound tert-butyl((3R,4S)-4-(1,3-dicarbonylisoindolin-2-yl)tetrahydrofuran-3-yl)carbamate(950 mg).

¹H NMR (400 MHz, Chloroform-d) δ 7.87 (m, 2H), 7.75 (m, 2H), 4.84 (d,J=9.5 Hz, 1H), 4.51 (t, J=8.0 Hz, 1H), 4.37 (t, J=8.3 Hz, 1H), 4.21-4.15(m, 1H), 4.09 (t, J=8.8 Hz, 1H), 3.85 (m, J=9.2, 6.4 Hz, 1H), 1.11 (s,9H).

MS m/z (ESI): 559.5 [M+H]⁺.

Step 3: Preparation of Tert-Butyl((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate

Tert-buty((3R,4S)-4-(1,3-dicarbonylisoindolin-2-yl)tetrahydrofuran-3-yl)carbamate(950 mg, 21%, 0.600 mmol) was dissolved in ethanol (6 mL), thenhydrazine hydrate (45 mg, 0.900 mmol) was added, the mixture was heatedto 75° C. and stirred for 2 h. The react ion was completed, then themixture was concentrated and separated by column chromatography (Eluent:DCM/MeOH 0-5%) to obtain compound tert-butyl((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate (120 mg, two-step yield:60/).

¹H NMR (400 MHz, Chloroform-d) δ 5.24 (s, 1H), 4.11 (s, 1H), 4.05 (m,1H), 4.00 (m, 1H), 3.63-3.52 (m, 2H), 3.49 (m, 1H), 1.46 (s, 9H).

Intermediates 368-375 were prepared referring to the synthesis method ofIntermediate 367.

Intermediate Compound MS: m/z No. structure Compound name [M + 1]⁺ 368

tert-butyl (3R,4S)-3-amino-4-(((2,2,2-trichloroeth-oxy)carbonyl)amino)pyrrolidine-1-carbox- ylate 377 369

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-methylpyrrolidin-3-yl) carbamate291 370

2,2,2-trichloroethyl ((3S,4R)-1-acetyl-4-aminopyrrolidin-3-yl) carbamate319 371

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-(2-(dimethylamino)ethyl)pyrrolidin-3-yl)carbamate 348 372

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-(methylaminoformyl)pyrrolidin-3-yl)carbamate 334 373

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-(oxetan-3-yl)pyrolidin-3-yl)carbamate 333 374

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-(1H-pyrazol-4-yl)pyr-rolidin-3-yl)carbamate 343 375

2,2,2-trichloroethyl ((3S,4R)-4-amino-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate 357

Preparation of Specific Examples Example 1 Preparation ofN-(2-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide

Step 1: Preparation of3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-7-((2-methyl-6-nitrophenyl)amino)-2,6-naphthyridin-1(2H)-one

7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(150 mg, 0.375 mmol) was dissolved in 14-dioxane (20 mL), then2-methyl-6-nitroaniline (114 mg, 0.751 mmol), cesium carbonate (367 mg,1.126 mmol), brett-phos (161 mg, 0.3 m mol) and Pd₂(dba)₃ (172 mg, 0.188mmol) were added. The gas was exchanged with N2, and the mixture washeated to 120° C. for 2 h. The reaction was completed, and the mixturewas concentrated and separated by silica gel column chromatography(Eluent: PE/EtOAc =2:1) to obtain compound3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methy-7-((2-methyl-6-nitrophenyl)amino)-2,6-naphthyridin-1(2H)-one(40 mg, yield: 21%). MS m/z (ESI): 516 [M+H]⁺.

Step 2: Preparation of7-((2-amino-6-methylphenyl)amino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one

3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-7-((2-methyl-6-nitrophenyl)amino)-2,6-naphthyridin-1(2H)-one(40 mg, 0.078 mmol) was dissolved in 10 mL of methanol, then 10 mg ofPd—C was added. The mixture was stirred at room temperature under H₂ for30 min. The reaction was completed, and the mixture was concentrated andseparated by silica gel column chromatography (Eluent: CH₂Cl₂/MeOH=10:1)to obtain compound7-((2-amino-6-methylphenyl)amino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(9.5 mg, yield:25%).

MS m/z (ESI): 486.4 [M+H]⁺.

Step 3: Preparation ofN-(2-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide

7-((2-amino-6-methylphenyl)amino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one(9.5 mg, 0.02 mmol) was dissolved in the mixture of THF and H₂O (4 mL/1mL), then sodium bicarbonate (9 mg, 0.104 mmol) was added, the mixturewas cooled with ice water bath, and the solution of acryloyl chloride inTHF (2 mg/2 mL, 0.02 mmol) was added dropwise. The mixture was stirredat 0° C. for 10 min. After the re action was completed, the mixture wasextracted for three times with dichloromethane. The organic phases werecombined, washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, filtrated and concentrated. Thecrude product was separated by silica gel column chromatography, toobtain compoundN-(2-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide(1 mg, yield: 9%).

¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.31 (s,1H), 7.10-7.05 (m, 2H), 6.68 (s, 1H), 6.52-6.48 (m, 1H), 6.44 (s, 1H),6.39 (s, 1H), 6.33 (d, J=1.4 Hz, 1H), 6.19 (d, J=10.2 Hz, 1H), 5.68 (dd.J=10.2, 1.4 Hz, 1H), 3.99 (s, 6H), 3.25 (s, 3H), 2.21 (s, 3H).

MS m/z (ESI): 541.4 [M+H]⁺.

Examples 2-75 were prepared referring to the synthesis method of Example1.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 2

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin- 3-yl)amino)-3-methylphe- nyl)acrylamide 5253

N-(2-((6-(cyclopropylmeth- yl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6- dihydro-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 579 4

N-(2-((6-(2-(tert-butylamino)- 2-oxoethyl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)- 5-oxo-5,6-dihydro-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 638 5

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-oxo-3,4-dihydropyrido[3,4-d] pyrimidin-6-yl)amino)-3-methyl- phenyl)acrylamide526 6

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-3-methyl-4-oxo-3,4-dihydropyrido [3,4-d]pyrimidin-6-yl)amino)-3-methylphenyl)acrylamide 540 7

N-(2-((3-(2,6-dichloro-3,5- dimethoxyphenyl)-1-oxo-1H-pyrano[4,3-c]pyridin-7-yl) amino)-3-methylphenyl) acrylamide 526 8

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydropyrido [3,4-d]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide 540 9

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-dimethoxy-2,6-naphthyridin-3-yl) amino)-3-methylphenyl)acryl- amide 539 10

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-methoxy-pyrido[3,4-d]pyrimidin- 6-yl)amino)-3-methylphenyl) acrylamide 540 11

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-3-(2-methoxyethyl)-4-oxo-3,4- dihydropyrido[3,4-d]pyrimidin-6-yl)amino)-3-methylphenyl) acrylamide 584 13

N-(-2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-3- methylphenyl)acrylamide 509 14

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)- 3-methylphenyl)acrylamide 510 15

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)- 5-(4-ethylpiperazin-1-yl) phenyl)acrylamide608 16

N-(2-((7-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-5-(4- ethylpiperazin-1-yl)-3-methylphenyl)acrylamide 589 17

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-5-(4- ethylpiperazin-1-yl)-3-methylphenyl)acrylamide 621 18

N-(2-((7-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-5-(4- ethylpiperazin-1-yl)phenyl) acrylamide575 19

N-(2-((7-(2,6-difluoro-3,5- dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-5-((4- methylpiperazin-1-yl)meth-yl)phenyl)acrylamide 575 20

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl)amino)-5-(4- ethylpiperazin-1-yl)phenyl) acrylamide 607 21

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl)amino)-5-(2- dimethylamino)dimethoxy) phenyl)acrylamide582 22

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl)amino)-5- morpholinophenyl)acrylamide 580 23

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl))amino)-5-((4- methylpiperazin-1-yl)meth-yl)phenyl)acrylamide 607 24

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl)amino)-5-(1- ethylpiperidin-4-yl)phenyl) acrylamide 606 25

N-(2-((5-((cyclopropylmeth- yl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 578 26

N-(2-((5-((cyclopropylmeth- yl)amino)-7-(2,6-dichloro-3,5-bis(dimethoxy-d₃)phenyl)- 2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 584 27

N-(2-((5-((cyclopropylmeth- yl)amino)-7-(2,6-difluoro-3,5-bis(dimethoxy-d₃)phenyl)- 2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 552 28

N-(2-((5-((cyclopropylmeth- yl)amino)-7-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6- naphthyridin-3-yl)amino-3-methylphenyl)acrylamide 546 29

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-hydroxyethyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 568 30

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-isopropylthio)ethyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 626 31

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-(ethylsulfonyl)ethyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 644 32

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-(dimethylamino)ethyl)amino)-2, 6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 595 33

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((3-(dimethylamino)propyl)amino)- 2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 609 34

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(meth-ylamino)-2,6-naphthyridin- 3-yl)amino)-3-methylphe- nyl)acrylamide 53835

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(ethyl-amino)-2,6-naphthyridin-3- yl)amino)-3-methylphenyl) acrylamide 552 36

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2,2,2-trifluoroethyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 606 37

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(dimeth-ylamino)-2,6-naphthyridin- 3-yl)amino)-3-methylphe- nyl)acrylamide 55238

N-(2-((5-((cyclopropylmeth- yl)(methyl)amino)-7-(2,6-dichloro-3,5-dimethoxyphe- nyl)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 592 39

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-(methylsulfonamido)ethyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 645 40

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 608 41

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((tetra-hydrofuran-3-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 608 42

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((oxetan-3-ylmethyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 594 43

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((tetra-hydro-2H-pyran-4-yl)meth- ylamino)-2,6-naphthyridin-3-yl)amino)-3-methylphe- nyl)acrylamide 622 44

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin- 3-yl))amino)-3-methyl- phenyl)acrylamide580 45

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((tetra-hydro-2H-pyran-4-yl)amino)- 2,6-naphthyridin-3-yl)amino)-3-methylphenyl)acryl- amide 608 46

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((tetra-hydrofuran-3-yl)amino)-2,6- naphthyridin-3-yl)amino)-3methylphenyl)acrylamide 594 47

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-methylpyrrolidin-3-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 621 48

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-methyl)pyrrolidin-2-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 621 49

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((1-methylpyrrolidin-3-yl)amino)- 2,6-naphthyridin-3-yl)amino)-3-methylphenyl)acryl- amide 607 50

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-methylazetidin-3-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 607 51

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((1-methylazetidin-3-yl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 593 52

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((1-methylpiperidin-4-yl)amino)-2, 6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 621 53

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-methylpiperidin-4-yl)methyl) amino)-2,6-naphthyridin-3-yl)amino)-3-methylphenyl) acrylamide 635 54

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((3,3-difluorocyclobutyl)amino)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 614 55

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((3,3-difluorocyclopentyl)amino)- 2,6-naphthyridin-3-yl)ami-no)-3-methylphenyl)acryl- amide 628 56

N-(2-((5-((cyclopentylmeth- yl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6- naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide 606 57

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(phen-ethylamino)-2,6-naphthyridin- 3-yl)amino)-3-methyl- phenyl)acrylamide628 58

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-methyl-1H-pyrazol-4-yl)meth- yl)amino)-2,6-naphthyridin-3-yl)amino)-3-methylphe- nyl)acrylamide 618 59

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-(2-hydroxyethyl)-1H-pyrazol- 4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)-3- methylphenyl)acrylamide 648 60

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(((1-(2-dimethoxyethyl)-1H-pyrazol- 4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)-3- methylphenyl)acrylamide 662 61

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-ethoxy-2,6-naphthyridin-3-yl) amino)-3-methylphenyl) acrylamide 553 62

N-(2-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-isopro-poxy-2,6-naphthyridin-3-yl)- amino)-3-methylphenyl) acrylamide 567 63

N-(2-((5-(cyclopropyl- methoxy)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naph- thyridin-3-yl)amino)-3-methylphenyl)acrylamide 579 64

N-(3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)- 1-methyl-1H-pyrazol-4-yl) acrylamide 500 65

N-(3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino- 1-(2-dimethoxyethyl)-1H-pyr-azol-4-yl)acrylamide 544 66

N-(3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-methoxy-pyrido[3,4-d]pyrimidin- 2-yl)amino)-1-methyl-1H- pyrazol-4-yl)acrylamide530 67

N-(3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-2,6-naph-thyridin-3-yl)amino)-1- methyl-1H-pyrazol-4-yl)acryl- amide 499 68

N-(3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-((2-methoxyethyl)amino)-2,6- naphthpyridin-3-yl)amino)-1-methyl-1H-pyrazol-4-yl) acrylamide 572 69

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)thieno[2,3-d]pyrimidin-2-yl)amino)- 3-methylphenyl)acrylamide 515 70

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)thieno[3,2-c]pyridin-6-yl)amino)-3- methylphenyl)acrylamide 515 71

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-5-yl)amino)- 3-methylphenyl)acrylamide 516 72

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)thiazolo[4,5-c]pyridin-6-yl)amino)- 3-methylphenyl)acrylamide 515 73

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-oxo-4H-1-pyrano[2,3-c]pyridin-6- yl)amino)-3-methylphenyl) acrylamide 526 74

N-(2-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-oxo-8H-pyrano[3,2-d]pyrimidin- 2-yl)amino)-3-methylphenyl) acrylamide 527 75

N-(2-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-3-methyl-4-oxo-3,4-dihydropyrido [3,4-d]pyrimidin-6-yl)amino)-3-methyl-5-(4-methyl- piperazin-1-yl)phenyl) acrylamide 638

Example 76 Preparation ofN-(3-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-4-yl)acrylamide

Step 1: Preparation ofN-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine

N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine(210 mg, 0.465 mmol) was dissolved in dichloromethane (6 mL), thenm-chloroperoxybenzoic acid (200 mg, 1.163 mmol) was added, and themixture was stirred at room temperature for 18 h. After the reaction wascompleted, a saturated sodium sulfite solution (5 mL) was added, and themixture was stirred for 5 min and extracted with dichloromethane, theorganic phase was washed successively with a saturated sodiumbicarbonate solution and then saturated brine, dried over anhydroussodium sulfate, filtrated, concentrated and separated by columnchromatography (Eluent: PE/EA=2/1) to obtain compoundN-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine(186 mg, yield: 82.7%).

MS m/z (ESI): 483.4 [M+H]⁺.

Step 2: Preparation ofN⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N²-(1-methy-4-nitro-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine

N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine(90 mg, 0.186 mmol) was dissolved in dried DMF (5 mL), and NaH (15 mg,0.372 mmol) was added at 0° C., and the mixture was stirred at roomtemperature for 10 min. Then 1-methyl-4-nitro-1H-pyrazol-3-amine (32 mg,0.223 mmol) was added, and the mixture was stirred at room temperaturefor 3 h. The mixture was quenched with a saturated aqueous ammoniumchloride, extracted with ethyl acetate and separated by silica gelcolumn chromatography (PE/EA=1/1) to obtain compoundNe-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N²-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine (100 mg, yield:98%). MS m/z (ESI): 545 [M+H].

Step 3: preparation ofN-(4-amino-1-methyl-H-pyrazol-3-yl)-N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]imidine-2,8-diamine

N⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N²-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine(40 mg, 0.074 mmol) was dissolved in methanol (10 mL), and thentriethylamine (3 drops) and Pd/C (20 mg, 10% content) were successivelyadded, and the mixture was stirred at room temperature under H₂ for 45min. The reaction was completed and the mixture was filtrated andseparated by silica gel column chromatography (DCM/MeOH) to obtaincompoundN²-(4-amino-1-methyl-H-pyrazol-3-yl)-N⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine(30 mg, yield:80%). MS m/z (ESI): 515 [M+H]⁺.

Step 4: Preparation ofN-(3-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-4-yl)acrylamide

N²-(4-amino-1-methyl-1H-pyrazol-3-yl)-N^(B)-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine (30 mg, 0.058 mmol) wasdissolved in the mixture of THF and H₂O (8 mL/2 mL), then NaHCO₃ (33 mg,0.39 mmol) was added, and acetyl chloride (7 mg, 0.078 mmol, dissolvedin 1 mL of THF) was added dropwise under ice bath, and the mixture wasstirred for 10 minutes, a saturated aqueous sodium bi carbonate solution(20 mL) was added, and the mixture was extracted with ethyl acetate andseparated by silica gel column chromatography (PE/EA=1/1) to obtaincompoundN-(3-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-methyl-H-pyrazol-4-yl)acrylamide(10 mg, yield:22%). MS m/z (ESI): 569 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.17 (s, 1H), 6.77 (s, 1H), 6.63(s, 1H), 6.38 (d, J=16.6 Hz, 2H), 6.33-6.24 (m, 1H), 5.70 (d, J=10.1 Hz,1H), 3.95 (s, 6H), 3.87 (s, 3H), 3.53-3.36 (m, 2H), 1.19-1.10 (m, 1H),0.55-0.41 (m, 2H), 0.42-0.29 (m, 2H).

Examples 77-117 were prepared referring to the synthesis method ofExample 76.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 77

N-(2-((8-((cyclopropylmethyl)ami- no)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2- yl)amino)-3-methylphenyl)acryl- amide579 78

N-(2-((8-((cyclopropylmethyl)ami- no)-6-(2,6-dichloro-3,5-bis(dimethoxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)-3-methylphenyl)acrylamide 585 79

N-(2-((8-((cyclopropylmethyl)ami- no)-6-(2,6-difluoro-3,5-bis(me-thoxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)-3-methylphenyl)acrylamide 553 80

N-(2-((8-((cyclopropylmethyl)ami- no)-6-(2,6-difluoro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2- yl)amino)-3-methylphenyl)acryl- amide547 81

N-(2-((6-(2,6-dichloro-3,5-dimethoxy- phenyl)-8-((2-hydroxyethyl)amino)pyrido[3,4-d]pyrimidin-2-yl- amino)-3-methylphenyl)acrylamide 56982

N-(2-((6-(2,6-dichloro-3,5-dimethoxy- phenyl))-8-((2-dimethoxyethyl))amino)pyrido[3,4-d]pyrimidin-2-yl)- amino)-3-methylphenyl)acrylamide 58383

N-(2-((6-(2,6-dichloro-3,5-dimethoxy- phenyl)-8-((2-(ethylsulfonyl)ethyl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)-3-methylphenyl)acrylamide 645 84

N-(2-((6-(2,6-dichloro-3,5-dimethoxy- phenyl)-8-((2-(dimethylamino)ethyl)amino)pyrido[3,4-d]pyrim- idin-2-yl)amino)-3-methylphenyl)acrylamide 596 85

N-(2-((6-(2,6-dichloro-3,5-dimethoxy- phenyl)-8-((3-(dimethylamino)propyl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide 610 86

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3- methylphenyl)acrylamide 539 87

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(ethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3- methylphenyl)acrylamide 553 88

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(ethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3- methylphenyl)acrylamide 607 89

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(dimethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)- 3-methylphenyl)acrylamide 553 90

N-(2-((8-((cyclopropylmethyl) (methyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d] pyrimidin-2-yl)amino-3-methylphenyl)acrylamide 593 91

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((2-(methylsulfon-amido)ethyl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 646 92

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((tetrahydrofuran-2-yl)methyl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 609 93

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((tetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methylphe-nyl)acrylamide 609 94

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((oxetan-3-ylmethyl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)-3-methylphenyl)acryl- amide595 95

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 623 96

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(oxetan-3-ylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)- 3-methylphenyl)acrylamide 581 97

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 609 98

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)-3-methylphenyl)acryl- amide595 99

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methylpyrrolidin-3-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 622 100

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methylpyrrolidin-2-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 622 101

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((1-methylpyrrolidin-3-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)-3-methylphenyl)acrylamide 608 102

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methylazetidin-3-yl)methyl)amino)pyrido[3,4-d] pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 608 103

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methylazetidin-3-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)-3-methylphenyl)acrylamide 594 104

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((1-methylpiperidin-4-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)-3-methylphenyl)acrylamide 622 105

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methylpiperidin-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)-3-methyl-phenyl)acrylamide 636 106

N-(2-((6-(2,6-dichloro-3,5-dime-thoxyphenyl)-8-((3,3-difluorocyclobutyl) amino)pyrido[3,4-d]pyrimidin-2-yl)amino-3-methylphenyl) acrylamide 615 107

N-(2-((6-(2,6-dichloro-3,5-dime-thoxyphenyl)-8-((3,3-difluorocyclopentyl) amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methylphenyl) acrylamide 629 108

N-(2-((8-((cyclopentylmethyl)ami- no)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2- yl)amino)-3-methylphenyl)acrylamide 607109

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(phenethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)- 3-methylphenyl)acrylamide 629 110

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-methyl-1H-pyr-azol-4-yl)methyl)amino)pyrido[3, 4-]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide 619 111

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methyl)amino) pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide 649 112

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-(((1-(2-dimethoxyethyl)-1H-pyrazol-4-yl)methyl)amino) pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide 663 113

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-methoxypyrido[3,4-d]pyrimidin-2-yl)amino)-3-methyl- phenyl)acrylamide 540 114

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-ethoxypyrido[3,4-d]pyrimidin-2-yl)amino)-3-methyl- phenyl)acrylamide 554 115

N-(2-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-isopropoxypyrido[3,4-d]pyrimidin-2-yl)amino)-3- methylphenyl)acrylamide 568 116

N-(2-((8-(cyclopropylmethoxy)-6- (2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl) amino)-3-methylphenyl)acrylamide 117

N-(3-((6-(2,6-dichloro-3,5-dime- thoxyphenyl)-8-((2-dimethoxyethyl)amino)pyrido[3,4-d]pyrimidin-2-yl) amino)-1-methyl-1H-pyrazol-4-yl)acrylamide 573

Example 118 Preparation of(±)—N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

Step 1: Preparation of(±)-(3S,4R)—N³-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydrofuran-3,4-diamine

2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine(40.0 mg, 0.108 m mol) and trans-tetrahydrofuran-3,4-diaminedihydrochloride (28.3 mg, 0.162 mmol) were dissolved in acetonitrile (2mL), then N,N-diisopropylethylamine (70 mg, 0.543 mmol) was added, themixture was heated to reflux for 16 h. After being cooled, the reactionliquid was diluted with EtOAc (10 mL), washed with saturated brine,dried over anhydrous sodium sulfate, filtrated, concentrated andseparated by PTLC (Eluent. CH₂Cl₂/MeOH=10:1) to obtain compound(3S,4R)—N-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydrofuran-3,4-diamine(30 mg, yield: 64%). MS m/z (ESI): 436.1 [M+H]⁺.

Step 2: Preparation of(±)—N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

(±)-(3S,4R)—N³-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydrofuran-3,4-diamine(30.0 mg, 0.069 mmol) was dissolved in the mixture THF and H₂O (1.2/0.3mL), NaHCO₃ (23.0 mg, 0.276 mmol) was added, and the mixture was cooledunder ice water bath, and then acryloyl chloride (6.8 mg, 0.076 mmol)was added. After addition, the mixture was stirred at 0° C. for 10 min.The reaction liquid was diluted with EtOAc (5 mL), washed with saturatedbrine, dried over anhydrous sodium sulfate, filtrated and concentrated.The crude product was separated by PTLC (Eluent: CH₂Cl₂/MeOH=10:1) toobtain compoundN-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide(17.4 mg, yield: 52%).

¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 9.16 (s, 1H), 7.55 (s, 1H), 6.68(s, 1H), 6.45 (d, J=7.3 Hz, 111), 6.27 (dd, J=17.0, 1.4 Hz, 1H), 6.07(dd, J=16.9, 10.3 Hz, 1H), 5.63 (dd, J=10.2, 1.4 Hz, 11), 4.94 (dd,J=11.6, 4.9 Hz, 11), 4.90-4.79 (m, 111), 4.34-4.19 (m, 2H), 3.98 (s,6H), 3.90-3.79 (m, 2H). MS m/z (ESI): 490.1 [M+H]⁺.

Example 119 Preparation ofN-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide

Step 1: Preparation ofN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine

2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine(100 mg, 0.27 m mol) was dissolved in NMP (3 mL), and Na₂CO₃ (143 mg,1.349 mmol) and (3S,4S)-4-azidotetrahydro-2H-pyran-3-amine hydrochloride(72 mg, 0.405 mmol) were added, the mixture was heated to 120° C. for 2h. The reaction was completed, and the mixture was cooled to roomtemperature, added with water, and extracted for three times with ethylacetate. The organic phases were combined, dried over anhydrous sodiumsulfate, filtrated, concentrated and separated by column chromatography(Eluent: petroleum ether/ethyl acetate 2:1) to obtain compoundN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine(38 mg, yield: 29%). MS m/z (ESI): 478.4 [M+H]⁺.

Step 2: Preparation of(3S,4S)—N³-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine

N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine(38 mg, 0.08 mmol) was dissolved in MeOH (8 mL), then Pd/C (10 mg) wasadded, and the mixture was stirred under H₂ at room temperature for 30min. The reaction was completed, and the mixture was concentrated andseparated by column chromatography (Eluent: dichloromethane/methanol10:1) to obtain compound(3S,4S)—N³-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine(12 mg, yield: 33%). MS m/z (ESI): 451.2 [M+H]⁺.

Step 3: Preparation ofN-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide

(3S,4S)—N³-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine(12 mg, 0.027 mmol) was dissolved in the mixture of THF and H₂O (4 mL/ImL), then NaHCO₃ (12 mg, 0.141 mmol) was added, the mixture was cooledunder ice water bath, and a solution of acryloyl chloride (3 mg, 0.027mmol) in THF (2 mL) was added dropwise, and the mixture was stirred atlow temperature for 10 min. After the reaction was completed, themixture was extracted three times with dichloromethane. The organicphases were combined, washed with saturated brine, dried over anhydroussodium sulfate, concentrated, and separated by column chromatography(Eluent: dichloromethane/petroleum ether (10:1)) to obtain compoundN-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide(6.3 mg, yield: 47%).

¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 2H), 7.56 (s, 1H), 6.68 (s, 1H), 6.25(dd, J=16.9, 1.4 Hz, 1H), 6.01 (dd, J=17.0, 10.3 Hz, 1H), 5.60 (dd,J=10.3, 1.4 Hz, 1H), 4.55 (s, 1H), 4.35 (s, 1H), 4.11-4.00 (m, 2H), 3.98(s, 6H), 3.78 (d, J=12.1 Hz, 1H), 3.64 (dd. J=13.4, 10.9 Hz, 1H),2.24-2.20 (m, 2H), 2.02-1.99 (m, 2H). MS m/z (ESI): 505.4 [M+H]⁺.

Examples 120-420 and 752 were prepared referring to the synthesis methodof Example 118 or 119.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 120

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-dime-thoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 458 121

N-((3R,4S)-4-((6-(2-chloro-3,5-dime-thoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 456 122

N-((3R,4S)-4-((6-(2-chloro-3,5-dime-thoxy-6-methyl)phenyl))pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 470 123

N-((3R,4S)-4-((6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrim-idin-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 474 124

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dime-thoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 489 125

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dime-thoxyphenyl)-5-((2-dimethoxyethyl)ami-no)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 562126

N-((3R,4S)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 558127

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dime-thoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 505 128

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dime-thoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-napthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 519129

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dime- thoxyphenyl)-5-methoxy-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl) acrylamide 519 130

N-((3R,4S)-4-((6-(2-chloro-6-cyclopropyl-3,5-dimethoxyphenyl)pyrido[3,4-d] pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 496 131

N-((3R,4S)-4-((6-(2-chloro-6-isopropyl-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 498 132

N-((3R,4S)-4-((7-(2-chloro-6-isopropyl-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acryl- amide 497 133

N-((3R,4S)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-difluoro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 526134

N-((3R,4S)-4-((5-(cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-bis(methoxy-d₃)phenyl)-2,6-naphthyridin-3-yl)ami- no)tetrahydrofuran-3-yl)acrylamide564 135

N-((3R,4S)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-difluoro-3,5-bis(methoxy-d₃)phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide532 136

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-hydroxyethyl)ami-no)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 548137

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(ethylsulfonyl)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 624 138

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(dimethylamino)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 575 139

N-((R,4S)-4-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(ethylamino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3- yl)acrylamide 532 140

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2,2,2-trifluoroethyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 586141

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(dimethylamino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 532 142

N-((3R,4S)-4-((5-((cyclopropylmethyl) methyl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 572 143

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(methylsulfonamido)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 625 144

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 588 145

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-3-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 588 146

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((oxetan-3-ylmethyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 574147

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 602 148

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)tetrahydrofu- ran-3-yl)acrylamide 560 149

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 574150

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)-2,6-naphthryridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 588 151

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-methylpiperidin-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 615 152

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((3,3-difluorocyclopentyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 608153

N-((3R,4S)-4-((5-((cyclopentylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 586154

N-((3R,4S)-4-((5-(benzylamino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 594 155

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 598 156

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-(2-hydroxyethyl)-pyrazol-4-yl)methyl)amino)-2,6- naphthyridin-3-yl)amino)tetrahydrafuran-3-yl)acrylamide 628 157

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-(2-methoxyethyl-)1H-pyrazol-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 642 158

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(4-methylpiperazin-1-yl)ethyl)amino)-2,6-naphthyridin-3-ylamino)tetrahydrofuran-3-yl)acrylamide 630 159

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-morpholinoethyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 617160

N-((3R,4S)-4-((7-(2-chloro-3-methoxy-phenyl)-5-((2-hydroxyethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro- furan-3-yl)acrylamide 484 161

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-((2-hydroxyethyl)ami-no)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 516162

N-((3R,4S)-4-((7-(2-fluoro-3-methoxy-phenyl)-5-((2-hydroxyethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 468 163

N-((3R,4S)-4-((7-(2-chloro-3,5-dimethoxy-phenyl)-5-((2-(dimethylamino)ethyl) amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 541 164

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-((2-(dimethylamino)ehyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide543 165

N-((3R,4S)-4-((5-((2-(dimethylamino)ethyl)amino)-7-(2-fluoro-3-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide495 167

N-((3R,4S)-4-((7-(2-fluoro-3,5-dimethoxy-phenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 538 168

N-((3R,4S)-4-((7-(2-fluoro-3-methoxy-phenyl)-5-(((tetrahydrofuran-2-yl)methylamino)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 508169

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-ethoxy-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 533 170

N-((3R,4S)-4-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-isopropoxy-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3- yl)acrylamide 547 171

N-((3R,4S)-4-((5-(cyclopropylmethoxy)-7-(2,6-dichloro-3,5-dimethoxyphenyl)2,6-naphthyridin-3-yl)amino)tetrahydro- furan-3-yl)acrylamide 559 172

N-((3S,4S)-3-((6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 488 173

N-((3S,4S)-3-((6-(6-chloro-7-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide498 174

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 520 175

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 534 176

N-((3S,4S)-3-((7-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 574 177

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 503 178

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-dimethoxyethyl)ami-no)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide576 179

N-((3S,4S)-3-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 572 180

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-dimethoxy-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 533 181

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)teahydro-2H- pyran-4-yl)acrylamide 519 182

N-((3S,4S)-3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide533 183

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)thieno[2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 509 184

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-5-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 510 185

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)thiazolo[4,5-c]pyridin-6-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 509 186

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridin-6-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 520 187

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-8H-pyrano[3,2-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 521 188

N-((3S,4S)-3-((6-(2-chloro-6-cyclopropyl-3,5-dimethoxyphenyl)pyrido[3,4-d] pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 510 189

N-((3S,4S)-3-((6-(2-fluoro-6-isopropyl-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 496 190

N-((3S,4S)-3-((6-(2-cyclopropyl-6-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 493 191

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 472 192

N-((3S,4S)-3-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 471 193

N-((3S,4S)-3-((7-(2-chloro-6-cyclopropyl-3,5-dimethoxyphenyl)-2,6-naphthyridin- 3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 509 194

N-((3S,4S)-3-((7-(2-cyclopropyl-6-fluoro-3,5-dimethoxyphenyl)-2,6-naphthyridin- 3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 493 195

N-((3S,4S)-3-((7-(2-fluoro-6-isopropyl-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 495 196

N-((3S,4S)-3-((7-(6-chloro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 496 197

N-((3S,4S)-3-((7-(6-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro- 2H-pyrah-4-yl)acrylamide 481 198

N-((3S,4S)-3-((5-((cyclopropylmethyl)amino)-7-(2,6-difluoro-3,5-dimethoxy-phenyl)-2,6-haphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide540 199

N-((3S,4S)-3-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-bis(methoxy-d₃)phenyl)-2,6-naphthyridin-3-yl)ami-no)tetrahydro-2H-pyran-4-yl)acrylamide 578 200

N-((3S,4S)-3-((5-((cyclopropylmethyl)amino)-7-(2,6-difluoro-3,5-bis(methoxy-d₃)phenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 546 201

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-hydroxymethyl)ami-no)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide562 202

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(dimethylamino)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 589 203

N-(3S,4S)-3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(methylamino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 532 204

N-((3S,4S)-3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-(ethylamino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 546 205

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2,2,2-trifluoroethyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide600 206

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(dimethylamino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 546 207

N-((3S,4S)-3-((5-((cyclopropylmethyl)(methyl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 586 208

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(methylsulfonamido)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 639 209

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)amino)-2,6-naphthyridin-3-yl) amino)tetrahydro-2H-pyran-4-yl)acrylamide 602 210

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-3-yl)methyl)amino)-2,6-naphthyridin-3-yl) amino)tetrahydro-2H-pyran-4-yl)acrylamide 602 211

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((oxetan-3-ylmethyl)amino)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide588 212

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 616 213

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-yl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 574 214

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide588 215

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydro-2H-pyran-4-yl)amino)-2,6-naphthyridin-3-yl))ami-no)tetrahydro-2H-pyran-4-yl)acrylamide 607 216

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-methylpiperidin-4-yl)methyl)amino)-2,6-naphthyridin-3- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 629 217

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((3,3-diftuorocyclopentyl)amino)-2,6-naphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide622 218

N-((3S,4S)-3-((5-((cyclopentylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 600 219

N-((3S,4S)-3-((5-(benzylamino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 608 220

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 612 221

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 642 222

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((1-(2-dimethoxyethyl)-1H-pyrazol-4-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 656 223

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-(4-methylpiperazin-1-yl)ethyl)amino)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 644 224

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((2-morpholinoethyl)amino)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide631 225

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-dimethoxy-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 547 226

N-((3S,4S)-3-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-5-isopropoxy-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 561 227

N-((3S,4S)-3-((5-(cyclopropylmethoxy)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 573 228

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyrrolidin-3-yl)acrylamide 489 229

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl) amino)pyrrolidin-3-yl)acrylamide488 230

N-((3S,4R)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl) amino)pyrrolidin-3-yl)acrylamide455 231

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)pyrrolidin- 3-yl)acrylamide 505 232

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)pyrrolidin-3-yl) acrylamide 504 233

N-((3S,4R)-4-((7-(2,6-dichloro-3,5- dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)pyrrolidin- 3-yl)acrylamide 518 234

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-8H-pyrano[3,4-d]pyrimidin-2-yl)amino)pyrrolidin-3-yl) acrylamide 506 235

N-((3S,4R)-4-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-oxo-1H-pyrano[4,3-c]pyridin-7-yl)amino)pyrrolidin-3-yl)acrylamide 505 236

N-((3S,4R)-4-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-oxo-1H-pyrano[4,3-c]pyridin-7-yl)amino)pyrrolidin-3-yl)acrylamide 472 237

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-1-methylpyrrolidin-3-yl)acrylamide 502 238

N-((3S,4R)-1-acetyl-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)pyrrolidin-3-yl)acrylamide 530 239

N-((3S,4R)-1-acetyl-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(methylamino)-2,6-naphthyridin-3-yl)amino)pyrrolidin- 3-yl)acrylamide 559 240

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-1-(2-(dimethylamino)ethyl) pyrrolidin-3-yl)acrylamide 559 241

(3S,4R)-3-acrylamido-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-N-methylpyrrolidine-1- carboxamide 545 242

(3S,4R)-3-acrylamido-4-((5-((cyclopropyl-methyl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)-N-methylpyrrolidine-1-carboxamide 614 243

N-((3S,4R)-1-acetyl-4-((5-((cyclopropyl-methyl)amino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl) amino)pyrrolidin-3-yl)acrylamide599 244

N-((3S,4R)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)-1-(oxetan-3-yl)pyrrolidin-3-yl)acrylamide 613 245

N-((3S,4R)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino-1-(2-(dimethylamino)ethyl)pyrrolidin-3- yl)acrylamide 628 246

N-((3S,4R)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)-1-(1H-pyrazol-4-yl)pyrrolidin-3-acrylamide 623 247

N-((3S,4R)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3- yl)acrylamide 637 248

N-((3S,4R)-4-((5-((cyclopropylmethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino)-1- methylpyrrolidin-3-yl)acrylamide571 249

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)-1-methylpyrrolidin-3-yl)acrylamide 601 250

(3S,4R)-3-acrylamido-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin- 3-yl)amino)-N-methylpyrrolidine-1-carboxamide 644 251

N-((3S,4R)-1-acetyl-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)pyrrolidin-3-yl)acrylamide 629 252

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl))-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)-1-(oxetan-3-yl)pyrrolidin-3-yl) acrylamide 643 253

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl) amino)-1-(2-(dimethylamino)ethyl)pyrrolidin-3-yl)acrylamide 658 254

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl)amino)-1H-pyrazol-4-yl)pyrrolidin-3- yl)acrylamide 653 255

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(((tetrahydrofuran-2-yl)methyl)amino)-2,6-naphthyridin-3-yl) amino)-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)acrylamide 667 256

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-methyl- pyrrolidin-3-yl)acrylamide 573 257

(3S,4R)-3-acrylamido-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-yl-amino)-2,6-naphthyridin-3-yl)amino)- N-methylpyrrolidine-1-carboxamide616 258

N-((3S,4R)-1-acetyl-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-yl- amino)-2,6-naphthyridin-3-yl)amino)pyrrolidin-3-yl)acrylamide 601 259

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-(oxetan-3- yl)pyrrolidin-3-yl)acrylamide615 260

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-(2-(dimethyl-amino)ethyl)pyrrolidin-3-yl)acrylamide 630 261

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)acrylamide 625 262

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(oxetan-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)acrylamide 639 263

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino)- 1-methylpyrrolidin-3-yl)acrylamide587 264

(3S,4R)-3-acrylamido-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino)-N-methylpyrrolidine-1-carboxamide 630 265

N-((3S,4R)-1-acetyl-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl) amino)pyrrolidin-3-yl)acrylamide 615266

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino)-1-(oxetan-3-yl)pyrrolidin-3-yl)acrylamide 629 267

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-yl)amino)-2,6-naphthyridin-3-yl)amino)-1-(2-(dimethylamino)ethyl)pyrrolidin-3- yl)acrylamide 644 268

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-ylamino)-2,6-naphthyridin-3-yl)amino)- 1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)acrylamide 639 269

N-((3S,4R)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-((tetrahydrofuran-3-ylamino)-2,6-naphthyridin-3-yl)amino)-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin- 3-yl)acrylamide 653 270

N-((3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2yl)amino)piperidin-4-yl)acrylamide 503 271

N-((3R,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)piperidin-4-yl)acrylamide 470 272

N-((3R,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl) amino)piperidin-4-yl)acrylamide502 273

N-((3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)piperidin- 4-yl)acrylamide 519 274

N-((3R,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)amino)piperidin-4-yl) acrylamide 518 275

N-((3R,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-7-methyl-8-oxo-7,8-hydropyrido[3,4-d]pyrimidin-2-yl)amino) piperidin-4-yl)acrylamide 533276

N-((3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-8H-pyrano[3,4-d]pyrimidin-2-yl)amino)piperidin-4-yl) acrylamide 520 277

N-(3R,4S)-3-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-oxo-1H-pyrano[4,3-c]pyridin-7-yl)amino)piperidin-4-yl) acrylamide 519 278

N-((3R,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-oxo-8H-pyrano[3,4-d]pyrimidin-2-yl)amino)piperidin-4-yl)acrylamide 487 279

N-((3R,4S)-4-((5-(((S)-1-cyclopropyl-ethyl)amino)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 572280

N-((3R,4S)-4-((5-(((S)-1-cyclopropyl-ethyl)amino)-7-(2,6-difluoro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 540281

N-((3R,4S)-4-((5-(cyclopropylamino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 544 282

N-((3R,4S)-4-((5-(cyclopropylamino)-7-(2,6-difluoro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-ylamino)tetrahydrofuran- 3-yl)acrylamide 512 283

N-((3R,4S)-4-((5-(azetidin-1-yl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3- yl)acrylamide 544 284

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxyazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 574285

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(3-methoxyazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 542286

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-(dimethylamino)azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 587 287

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-(trifluoromethyl)azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 612 288

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3,3-dimethylazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 572289

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3,3-difluoroazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 580290

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-hydroxy-3-methyl-azetidin-1-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 574 291

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxy-3-methyl-azetidin-1-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 588 292

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(3-dimethoxy-3-methyl-azetidin-1-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 556 293

N-((3R,4S)-4-((5-(3-cyano-3-methyl-azetidin-1-yl)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 583294

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 586 295

N-(3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(2-(2-6-azaspiro[3.3]heptan-6-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 554 296

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(1-oxa-6-azaspiro[3.3]heptan-6-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 586 297

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(1-oxa-6-azaspiro[3.3]heptan-6-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 554 298

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-azaspiro[3.3]heptan-2-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 584299

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-azaspiro[3.4]octan-2-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 598300

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(6-oxa-2-azaspiro[3,4]octan-2-yl)-2,6-naphthyridin-3-yl))amino)tetrahydrofuran-3-yl)acrylamide 600 301

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide614 302

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(pyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran- 3-yl)acrylamide 558 303

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-methoxypyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 588304

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(3-methoxypyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 556305

N-((3R,4S)-4-((5-(3-cyanopyrrolidin-1-yl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahy- drofuran-3-yl)acrylamide 583 306

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3,3-difluoropyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 594307

N-(3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxy-3-methyl-pyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 602 308

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(3-methoxy-3-methyl-pyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 570 309

N-((3R,4S)-4-((5-(3-cyano-3-methyl-pyrrolidin-1-yl)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 597310

N-((3R,4S)-4-((5-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 570311

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide614 312

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-morpholino-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3- yl)acrylamide 574 313

N-((3R,4S)-4-((7-(2,6-difluoro-3,5- dimethoxyphenyl)-5-morpholino-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3- yl)acrylamide 542 314

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-methylmorpholino)-2,6-naphthyridin-3-yl)amino)tetrahydro- furan-3-yl)acrylamide 588 315

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(2-methylmorpholino)-2,6-naphthyridin-3-yl)amino)tetrahydro- furan-3-yl)acrylamide 556 316

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2,6-dimethylmorpholino)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 602 317

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(2,6-dimethylmorpholino)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 570 318

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-hydroxypiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 588319

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-dimethoxypiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 602320

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(4-dimethoxypiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 570321

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-methoxypiperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydrofuran-3-yl)acrylamide 602322

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-hydroxy-4-methyl-piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 602 323

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-methoxy-4-methyl-piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 616 324

N-((3R,4S)-4-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5-(4-methoxy-4-methyl-piperidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydrofuran-3-yl)acrylamide 584 325

N-((3R,4S)-4-((5-(4-cyano-4-methyl-piperidin-1-yl)-7-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,6-naphthyridin-3-yl)amino) tetrahydrofuran-3-yl)acrylamide 611326

N-(7-(((3S,4R)-4-acrylamidotetrahydro-furan-3-yl)amino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-1-yl) cyclopropanecarboxamide 572 327

N-(7-(((3S,4R)-4-acrylamidotetrahydro- furan-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-1-yl) tetrahydrofuran-2-carboxamide602 328

N-((3R,4S)-4-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(methylsulfonamido)-2,6-naphthyridin-3-yl)amino)tetrahydro- furan-3-yl)acrylamide 582 329

N-((3S,4S)-3-((5-(cyclopropylamino)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 558 330

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-methoxyazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide588 331

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3,3-difluoroazetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide594 332

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxy-3-methyl-azetidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 602 333

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 600 334

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 614 335

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 628 336

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxypyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide602 337

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(3-dimethoxy-3-methyl-pyrrolidin-1-yl)-2,6-naphthyridin-3-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 616 338

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(2,6-dimethylmorpholino)-2,6-naphthyridin-3-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide 616339

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-2,6-naphthyridin-3-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide616 340

N-((3S,4S)-3-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-(4-dimethoxy-4-methyl-piperidin-1-yl)-2,6-naphthyridin-3-yl)ami-no)tetrahydro-2H-pyran-4-yl)acrylamide 630 341

N-((3R,4S)-4-((4-((cyclopropylmethyl)amino)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 559 342

N-((3R,4S)-4-((4-((cyclopropylmethyl)amino)-2-(2,6-difluoro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)ami- no)tetrahydrofuran-3-yl)acrylamide 527 343

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((2-dimethoxyethyl)ami-no)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide563 344

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide575 345

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((tetrahydroturan-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 589 346

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 589 347

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-difluorocyclopentyl)amino)pyrido[3,4-d]pyrimidin-6-yl) amino)tetrahydrofuran-3-yl)acrylamide609 348

N-((3R,4S)-4-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(neopentylamino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydrofuran-3-yl)acrylamide 575349

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl) acrylamide 599 350

N-((3R,4S)-4-((4-(((S)-1-cyclopropyl-ethyl)amino)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 573 351

N-((3R,4S)-4-((4-(((S)-1-cyclopropyl-ethyl)amino)-2-(2,6-difluoro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 541 352

N-((3R,4S)-4-((4-(cyclopropylamino)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydrofuran-3-yl)acrylamide 545353

N-((3R,4S)-4-((4-(cyclopropylamino)-2-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydrofuran-3-yl)acrylamide 513354

N-((3R,4S)-4-((4-(azetidin-1-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran- 3-yl)acrylamide 545 355

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-dimethoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide575 356

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(3-dimethoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide543 357

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl) amino)tetrahydrofuran-3-yl)acrylamide588 358

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-(trifluoromethyl)azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 613 359

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-dimethylazetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide573 360

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)pyrido[3,4-d]pyritnidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide581 361

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-hydroxy-3-methyl-azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 575 362

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-methoxy-3-methyl-azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 589 363

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(3-dimethoxy-3-methyl-azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 557 364

N-((3R,4S)-(4-((4-(3-cyano-3-methyl-azetidin-1-yl)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 584 365

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 587 366

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 555 367

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 587 368

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 555 369

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-azaspiro[3.3]heptan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide585 370

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide599 371

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 601 372

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 615 373

N-(3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro- furan-3-yl)acrylamide 559 374

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide589 375

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(3-methoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide557 376

N-((3R,4S)-4-((4-(3-cyanopyrrolidin-1-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide 584377

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)ami- no)tetrahydrofuran-3-yl)acrylamide595 378

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-dimethoxy-3-methyl-pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 603 379

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(3-methoxy-3-methyl-pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 571 380

N-((3R,4S)-4-((4-(3-cyano-3-methyl-pyrrolidin-1-yl)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 598 381

N-((3R,4S)-4-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 571 382

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 615 383

N-(3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-morpholinopyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran- 3-yl)acrylamide 573 384

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-morpholinopyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran- 3-yl)acrylamide 543 385

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-methylmorpholino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide 589386

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(2-methylmorpholino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide 557387

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2,6-dimethylmorpholino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide 603388

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(2,6-dimethylmorpholino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide 571389

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-hydroxypiperidin-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide589 390

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide603 391

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide571 392

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-dimethoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydrofuran-3-yl)acrylamide603 393

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-hydroxy-4-methyl-piperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 603 394

N-(3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-dimethoxy-4-methyl-piperidin-1-yl)pyrido[3,4-d]pyrimidin-6-ylamino)tetrahydrofuran-3-yl)acrylamide 617 395

N-((3R,4S)-4-((2-(2,6-difluoro-3,5-dimethoxyphenyl)-4-(4-dimethoxy-4-methyl-piperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 585 396

N-((3R,4S)-4-((4-(4-cyano-4-methyl-piperidin-1-yl)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydrofuran-3-yl)acrylamide 612 397

N-(6-(((3S,4R)-4-acrylamidotetrahydro-furan-3-yl)amino)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin- 4-yl)cyclopropanecarboxamide 573398

N-(6-(((3S,4R)-4-acrylamidotetrahydro-furan-3-yl)amino)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-yl)tetrahydrofuran-2-carboxamide 603 399

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(methylsulfonamido)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydrofuran-3-yl)acrylamide 583400

N-((3S,4S)-3-((4-((cyclopropylmethyl)amino)-2-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 573 401

N-((3S,4S)-3-((4-((cyclopropylmethyl)amino)-2-(2,6-difluoro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 541 402

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((2-methoxyethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide577 403

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 589 404

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl))-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 603 405

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 603 406

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-((3,3-difluorocyclopentyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 623 407

N-((3S,4S)-3-((2-(2,6-dichloro-3,5- dimethoxyphenyl)-4-(neopentylamino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide589 408

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 613 409

N-((3S,4S)-3-((4-(cyclopropylamino)-2-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide559 410

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 589 411

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 595 412

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-dimethoxy-3-methyl-azetidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl-amino)tetrahydro-2H-pyran-4-yl)acrylamide 603 413

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 601 414

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 615 415

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)letrahydro-2H-pyran-4-yl)acrylamide 629 416

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-dimethoxypyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 603 417

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(3-methoxy-3-methyl-pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 617 418

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(2,6-dimethylmorpholino)pyrido[3,4-d]pyrimidin-6-yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide617 419

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-hydroxy-4-methyl-piperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 617 420

N-((3S,4S)-3-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(4-dimethoxy-4-methylpiperidin-1-yl)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 631 752

N-((3R,4S)-4-((2-(2,6-dichloro-3,5-dimethoxyphenyl)-4-(methylamino)pyrido[3,4-d]pyrimidin-6-yl)amino)tetrahydro- furan-3-yl)acrylamide 519

Example 421 Preparation ofN-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

Step 1: preparation ofN-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine

N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8-amine (210 mg, 0.465 mmol) was dissolved in dichloromethane(6 mL), then m-chloroperoxybenzoic acid (200 mg, 1.163 mmol) was added,and the mixture was stirred at room temperature for 18 h. After thereaction was completed, a saturated sodium sulfite solution was added,and then the mixture was stirred for 5 min and extracted withdichloromethane, the organic phase was washed with a saturated sodiumbicarbonate and then saturated brine, dried over anhydrous sodiumsulfate, filtrated, concentrated, and separated by column chromatography(Eluent: PE/EA=2/1) to obtain compoundN-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine(186 mg, yield: 82.7%).

MS m/z (ESI): 483.4 [M+H]⁺.

Step 2: Preparation of(±)—N²-((3S,4R)-4-aminotetrahydrofuran-3-yl)-N⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine-8-amine(190 mg, 0.393 mmol) and (3R,4S)-tetrahydrofuran-3,4-diaminedihydrochloride (206 mg, 1.179 mmol) were dissolved in acetonitrile (6mL), then N,N-diisopropylethylamine (507 mg, 3.93 mmol) was added, andthe mixture was heated to reflux, an d stirred for 20 h. The reactionwas completed, and the mixture was cooled to room temperature. Thereaction liquid was diluted with EtOAc (20 mL), washed with saturatedbrine, dried over anhydrous sodium sulfate, filtrated, concentrated, andseparated by TLC (dev eloping agent: CH₂Cl₂/MeOH 10/1) to obtaincompound(±)—N²-((3S,4R)-4-aminotetrahydrofuran-3-yl)-N⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine(120 mg, yield: 60%).

MS m/z (ESI): 505.4 [M+H]⁺.

Step 3: Preparation of(±)—N-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

At 0° C., acryloyl chloride (22.6 mg, 0.249 mmol) was added to thesolution of(±)—N²-((3S,4R)-4-aminotetrahydrofuran-3-yl)-N⁸-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine(120 mg, 0.237 mmol) and sodium bicarbonate (79.6 mg, 0.948 mmol) in themixture of tetrahydrofuran (6.4 mL) and water (1.6 mL). After addition,the mixture was stirred at 0° C. for 5 min. The reaction liquid wasdiluted with EtOAc (10 mL), washed with saturated brine, dried overanhydrous sodium sulfate, filtrated, concentrated and separated by TLC(Eluent: CH₂Cl₂/MeOH=20/1) to obtain compound(+)—N-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide (93mg, yield: 70%).

¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.80 (brs, 1H), 6.68 (s, 1H),6.62 (s, 1H), 6.38 (brs, 1H), 6.21 (dd, J=17.0, 1.5 Hz, 1H), 6.02 (dd,J=17.0, 10.2 Hz, 1H), 5.56 (dd, J=10.1, 1.5 Hz, 1H), 4.93-4.83 (m, 2H),4.30-4.18 (m, 2H), 3.96 (s, 6H), 3.90 (dd, J=9.7, 3.2 Hz, 1H), 3.79 (dd,J=9.2, 5.2 Hz, 1H), 3.52-3.37 (m, 2H), 0.88 (t, J=6.0 Hz, 1H), 0.57-0.48(m, 2H), 0.36-0.26 (m, 2H). MS m/z (ESI): 559.5 [M+H]⁺.

Step 4: Preparation ofN-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

(±)—N-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide(93 mg, 0.166 mmol) was separated by chiral HPLC to obtainN-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide(43.5mg, ee value>98%, yield: 46.8%) andN-((3S,4R)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide(39 mg, ee value>98%, yield: 41.9%).

Example 433 Preparation ofN-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

Step 1: Preparation of8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

The compound was prepared referring to the synthesis method of step 1 ofExample 421.

Step 2: Preparation of Tert-Butyl((3R,4S)-4-((S-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate

8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(409 mg, 0.912 mmol) and tert-butyl((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate (553 mg, 2.736 mmol) weredissolved in acetonitrile (50 mL), then trifluoroacetic acid (31 mg,0.274 mmol) was added. The reaction liquid was stirred at 95° C. for 4h. After being cooled, the mixture was diluted with ethyl acetate (50mL), washed with a saturated sodium bicarbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, concentrated and separatedby column chromatography (CH₂Cl₂/MeOH 0-4%) to obtain compoundtert-butyl((3R,4S)-4-((8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate(414 mg, yield: 79.6%). MS m/z (ESI): 570.4, 57 2.4 [M+H]+.

Step 3: Preparation of Tert-Butyl((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate

A solution oftert-butyl((3R,4S)-4-((8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate(60 mg, 0.105 mmol) and meth ylamine (1.5 mL, 33% ethanol solution) inN-methylpyrrolidone (1 mL) was heated to 11 0° C. and stirred for 18 h.The reaction liquid was diluted with ethyl acetate (5 mL), washed withsaturated brine, dried over anhydrous sodium sulfate, concentrated, andseparated by using a preparative TLC (PE/EA=1:1) to obtain compoundtert-butyl((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate(32 mg, yield: 54%). MS m/z (ESI): 565.4, 567.4 [M+H]+.

Step 4: Preparation ofN²-((3S,4R)-4-aminotetrahydrofuran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N⁸-methylpyrido[3,4-d]pyrimidine-2,8-diamineTrifluoroacetate

A solution of tert-buty((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate(32 mg, 0.057 mmol) in the solution of trifluoroacetic acid indichloromethane (2 mL, 20%) was stirred at room temperature for 1 h, andthen concentrated to obtain an oil product which was directly use d inthe next step. MS m/z (ESI): 465.4, 467.4 [M+H]⁺.

Step 5: Preparation ofN-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide

At 0° C., acryloyl chloride (5.7 mg, 0.063 mmol) was added to a solutionofN²-((3S,4R)-4-aminotetrahydrofuran-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-methylpyrido[3,4-d]pyrimidine-2,8-diaminetrifluoroacetate (the crude product) and NaHCO₃ (57 mg, 0.684 mmol) inthe mixture of tetrahydrofuran (3.2 mL) and water (0.8 mL). Afteraddition, the mixture was stirred at 0° C. for 5 min. The reactionliquid was diluted with EtOAc (mL), washed with a saturated sodiumbicarbonate and saturated brine, dried over anhydrous sodium sulfate,concentrated and separated by using a preparative TLC (CH₂Cl₂/MeOH 20:1)to obtain compoundN-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide(17.6 mg, yield: 59.5%).

¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 6.30(brs, 1H), 6.19 (d, J=16.9 Hz, 1H), 5.97 (dd, J=17.0, 10.3 Hz, 1H), 5.88(brs, 1H), 5.54 (d, J=10.4 Hz, 1H), 4.95-4.83 (m, 2H), 4.29-4.18 (m,2H), 3.95 (s, 6H), 3.89 (dd, J=9.7, 3.0 Hz, 1H), 3.77 (dd, J=9.3, 5.5Hz, 1H), 3.14 (d, J=4.4 Hz, 3H). MS m/z (ESI): 519.4, 521.4 [M+H]⁺.

Example 775N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide

Step 1: Preparation of8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine(930 mg, 2.42 mmol) was dissolved in DCM (50 mL), and m-CPBA (1.23 g,6.05 mmol) was added, and the mixture was stirred at room temperaturefor 2 h. The reaction was completed, and sodium thiosulfate was added toquench the reaction. The mixture was extracted with DCM and separated bysilica gel column chromatography to obtain compound8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(800 mg, yield:79%). MS m/z (ESI): 416 [M+H]+.

Step 2: Preparation ofN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine

8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(1 g, 2.41 mmol) was dissolved in the mixture of tert-butyl alcohol (80mL) and DCE (20 mL), then DIPEA (1.55 g, 12.05 mmol) was added, themixture was heated to 90° C. and stirred overnight. The mixture wasextracted with DCM and separated by silica gel column chromatography toobtain compoundN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine(650 mg, yield:56%). MS m/z (ESI): 478 [M+H]+.

Step 3: Preparation ofN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidine-2-amine

N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine (325 mg, 0.68 mmol), 3-methoxyazetidinehydrochloride (25 2 mg, 2.04 mmol) and DIPEA (439 mg, 3.4 mmol) weredissolved in n-butanol (15 mL), the mixture was heated to 100° C. for 4h, and then the mixture was concentrated, extracted with ethyl acetateand separated by silica gel column chromatography to obtain compoundN-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidine-2-amine(350 mg, yield: 97%). MS m/z (ESI): 529 [M+H]+.

Step 4: Preparation of(3S,4S)—N³-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine

N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidine-2-amine(350 mg, 0.662 mmol) was dissolved in the mixture of THF (10 mL) andwater (1 mL), and then triphenylphosphine (521 mg, 1.99 mmol) was added,the mixture was heated to 80° C. and stirred for 16 h. The mixture wascooled, directly dried over anhydrous sodium sulfate, concentrated, andseparated by silica gel column chromatography to obtain compound(3S,4S)—N³-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine (290 mg, yield:87%). MS m/z (ESI), 503 [M+H]+.

Step 5: Preparation ofN-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide

(3S,4S)—N³-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine(290 mg, 0.58 mmol) was dissolved in the mixture of THF (20 mL) andwater (5 mL), then NaHCO₃ (243 mg, 2.89 mmol) was added, and acryloylchloride solution (63 mg, 0.69 mmol, dissolved in 1 mL THF) was addeddropwise at room temperature, the mixture was stirred at roomtemperature for 10 min. The reaction was completed determined by TLC, asaturated aqueous solution of NaHCO₃ was added to quench the reaction,the mixture was extracted with ethyl acetate, concentrated and separatedby silica gel column chromatography to obtain compoundN-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide(204 mg, yield:63%). MS m/z (ESI): 557 [M+H]+.

1H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 6.96 (s, 1H), 6.69 (t, J=8.0 Hz,H), 6.65 (s, 1H), 6.25 (dd. J=17.0, 1.4 Hz, 1H), 6.08 (s, 1H), 6.02 (dd.J=16.9, 10.3 Hz, 1H), 5.60 (dd, J=10.3, 1.4 Hz, 1H), 4.73 (brs, 1H),4.56 (brs, 1H), 4.42 (d, J=8.5 Hz, 1H), 4.39-4.22 (m, 4H), 4.05 (dd.J=12.0, 4.5 Hz, 1H), 3.99 (d, J=11.7 Hz, 1H), 3.92 (s, 6H), 3.75 (dd,J=11.9, 1.6 Hz, 1H), 3.65-3.57 (m, 1H), 3.33 (s, 3H), 2.09-2.02 (m, 1H),1.91-1.81 (m, 1H).

Examples 422-714 and 753-806 were prepared referring to the synthesismethod of Example 33, 421 or 775.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 422

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-methoxyethyl) amino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 563 423

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-methoxypyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 520 424

N-((3R,4S)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-difluoro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 527 425

N-((3R,4S)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-bis(meth-oxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 565 426

N-((3R,4S)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-difluoro-3,5-bis(meth-oxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 533 427

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-hydroxyethyl)a- mino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 549 428

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(isopropylthio)eth-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3-yl)acrylamide 607 429

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(ethylsulfonyl) ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 625 430

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((2-(methyl-sulfonamido)ethyl)a- mino)pyrido[3,4-d]pyri-midin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 626 431

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(dimethylami- no)ethyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 576 432

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3-(dimethylami- no)propyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 590 434

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(ethylamino)pyri- do[3,4-d]pyrimidin-2-yl0amino)tetra-hydrofuran-3-yl)acrylamide 533 435

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2,2,2-trifluoroeth-yl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3-yl)acryl-amide 587 436

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(dimethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 533437

N-((3R,4S)-4-((8-((cyclopropylmeth-yl)(methyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrim- idin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 573 438A

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((((R)-tetrahydro- furan-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 589 438B

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((((S)-tetrahydro- furan-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 589 439

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 3-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 589 440

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((oxetan-3-ylmeth- yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 575 441

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydro-2H- pyran-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 603 442

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(oxetan-3-yl-amino)pyrido[3,4-d]pyrimidin-2-yl) amino)tetrahydrofuran-3-yl)acrylamide561 443

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 575 444

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 589 445

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-methyl-pyrrolidin-3-yl)meth- yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 602 446

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-methyl-pyrrolidin-2-yl)methyl)a- mino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 602 447

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((1-methyl-pyrrolidin-3-yl)a- mino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 588 448

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylazeti- din-3-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 588 449

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylazetidin- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 574 450

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylpiperi- din-4-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 602 451

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylpiper- idin-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 616 452

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3,3-difluorocyclo-butyl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3-yl)acrylamide 595 453

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3,3-difluorocyclo- pentyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 609 454

N-((3R,4S)-4-((8-((cyclopentylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 587 455

N-((3R,4S)-4-((8-(benzylamino)-6- (2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidn-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 595456

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(phenethylamino)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 609457

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(phenylamino)pyri- do[3,4-d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 581 458

N-((3R,4S)-4-((8-((3-aminobenzyl)a- mino)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 610 459

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 599 460

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl)methyl)amino) pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 629 461

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-(2-methoxy-ethyl)-1H-pyrazol-4-yl)methyl)amino) pyrido[3,4-d]pyrimidin-2-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 643 462

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 575463

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((3-(isopropyl-amino)propyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 604 464

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(isopropyl-amino)butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 618 465

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((4-(dimethylamino) butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 604 466

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((4-(pyrrolidin-1- yl)butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 630 467

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((2-(4-methyl-piperazin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 631 468

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-morpholinoeth- yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 618 469

N-((3R,4S)-4-((8-((2-(3-amino- pyrrolidin-1-yl)ethyl)amino)-6-(2,6-dichloro-3,5-dimethoxy- phenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 617 470

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(3-(dimethyl- amino)pyrrolidin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 645471

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(2-(dimethyl- amino)ethoxy)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 620 472

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(2-(hydroxy-methyl)pyrrolidin-1-yl)butyl)amino) pyrido[3,4-d]pyrimidni-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 660 473

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((4-(3,3-difluoro-pyrrolidin-1-yl)butyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 666 474

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(3-methoxy-pyrrolidin-1-yl)butyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 660 475

N-((3R,4S)-4-((6-(2-chloro-3,5-dimeth-oxyphenyl)-8-((cyclopropylmethyl)a- mino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 525 476

N-((3R,4S)-4-((8-((cyclopropylmeth- yl)amino)-6-(2-fluoro-3-methoxyphen-yl)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide479 477

N-((3R,4S)-4-((6-(2-chloro-3-(meth- oxy-d₃)phenyl)-8-((cyclopropylmeth-yl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3-yl)acryl-amide 498 478

N-((3R,4S)-4-((8-((cyclopropylmeth- yl)amino)-6-(2-fluoro-3-(methoxy-d3)phenyl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 482 479

N-((3R,4S)-4-((6-(2-chloro-3,5-bis (methoxy-d₃)phenyl)-8-((cylcopropyl-methyl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3-yl)acrylamide 531 480

N-((3R,4S)-4-((8-((cyclopropylmeth- yl)amino)-6-(2-fluoro-3,5-bis(meth-oxy-d₃)phenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 515 481

N-((3R,4S)-4-((6-(2-chloro-3-meth- oxyphenyl)-8-(((tetrahydrofuran-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 525 482

N-((3R,4S)-4-((6-(2-chloro-3-meth- oxyphenyl)-8-(((1-methylpyrrolidin-2-yl)methyl)amino)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 538 483

N-((3R,4S)-4-((6-(2-fluoro-3-meth- oxyphenyl)-8-(((1-methylpyrrolidin-2-yl)methyl)amino)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 522 484

N-((3R,4S)-4-((6-(2-chloro-3,5-dimeth-oxyphenyl)-8-(((1-methylpyrrolidin- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 568 485

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((1-methylpyrrol- idin-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 570 486

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 557 487

N-((3R,4S)-4-((6-(2-chloro-3,5-dimeth- oxyphenyl)-8-((tetrahydro-2H-py-ran-4-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 555 488

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((2-(4-methylpiper- azin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 599 489

N-((3R,4S)-4-((6-(2-chloro-3-meth- oxyphenyl)-8-((2-(4-methylpiperazin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 567 490

N-((3R,4S)-4-((6-(2-chloro-3,5-dimeth-oxyphenyl)-8-((2-(4-methylpiperazin- 1-yl)ethyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 597 491

N-((3R,4S)-4-((6-(3,5-dimethoxyphen-yl)-8-((2-(4-methylpiperazin-1-yl)eth-yl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3-yl)acryl-amide 563 492

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((2-methoxyethyl) amino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 531 493

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((1-methylpiperi- din-4-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 570 494

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 567 495

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 557 496

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-ethoxypyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 534 497

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-isopropoxy-pyrido[3,4-d]pyrimidin-2- yl)amino)tetra-hydrofuran-3-yl)acryl- amide548 498

N-((3R,4S)-4-((8-(cyclopropylmethoxy)-6-(2,6-dichloro-3,5-dimethoxyphen-nyl)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide560 499

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((2-methoxyeth-yl)amino)pyrido[3,4-d]pyrimidin-2-yl) amino)tetrahydro-2H-pyran-4-yl)acrylamide 577 500

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-((2-methoxyeth-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acryl- amide 545 501

N-((3S,4S)-3-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 573 502

N-((3S,4S)-3-((8-((cyclopropylmeth-yl)amino)-6-(2,6-difluoro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 541 503

N-((3S,4S)-3-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-bis(meth-oxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 579 504

N-((3S,4S)-3-((8-((cyclopropylmeth-yl)amino)-6-(2,6-difluoro-3,5-bis(meth-oxy-d₃)phenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 547 505

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-hydroxyethyl) amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acryl- amide 563 506

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(isopropylthi-o)ethyl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 621 507

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(ethylsulfonyl)eth-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 639 508

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(dimethylami- no)ethyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 590 509

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3-(dimethylami- no)propyl)amino)pyrido[3,4-d]pyrim-idin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 604 510

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(methylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide549 511

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(ethylamino)pyri- do[3,4-d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 547 512

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2,2,2-trifluoroeth-yl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 601 513

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(dimethylamino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide547 514

N-((3S,4S)-3-((8-((cyclopropylmeth-yl)(methyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydro-2H-py-ran-4-yl)acrylamide 587 515

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((2-(methyl-sulfonamido)ethyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 640 516

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidn-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 603 517

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 571 518

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 3-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 603 519

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((oxetan-3-ylmeth- yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 589 520

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydro-2H- pyran-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 617 521

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(oxetan-3-ylami-no)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydro-2H-pyran-4-yl)acryl-amide 575 522

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphennyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 589 523

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 557 524

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 603 525

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 571 526

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylpyrroli- din-3-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 616 527

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((1-methylpyrroli- din-3-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 584 528

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylpyrroli- din-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 616 529

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((1-methylpyrroli- din-2-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 584 530

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylpyrroli- din-3-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 602 531

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((1-methylpyrroli- din-3-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 570 532

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylazeti-din-3-yl)methyl)amino)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 602 533

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((1-methylazeti-din-3-yl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 588 534

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylpiperi- din-4-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 616 535

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((1-methylpiperi- din-4-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 584 536

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylpiperi- din-4-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 630 537

N-((3S,4S)-3-(((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3,3-difluorocyclo-butyl)amino)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 609 538

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((3,3-difluorocyclo- pentyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 623 539

N-((3S,4S)-3-((8-((cyclopentylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 601 540

N-((3S,4S)-3-((8-(benzylamino)-6- (2,6-dichloro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide609 541

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(phenethylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide623 542

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(phenylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide595 543

N-((3S,4S)-3-((8-((3-aminobenzyl)a- mino)-6-(2,6-dichloro-3,5-dimethoxy-phenyl))pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydro-2H-pyran-4-yl)acryl- amide 624 544

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 613 545

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 581 546

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl)methyl)amino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide643 547

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(((1-(2-methoxy-ethyl)-1H-pyrazol-4-yl)methyl)amino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydroxy-2H-pyran-4-yl)acrylamide657 548

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(neopentylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide589 549

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((3-(isopropyl-amino)propyl)amino)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 618 550

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(isopropyl-amino)butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 632 551

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(dimethyl-amino)butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 618 552

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((4-(pyrrolidin-1- yl)butyl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 644 553

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((2-(4-methyl-piperazin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 645 554

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-morpholinoeth- yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 632 555

N-((3S,4S)-3-((8-((2-(3-aminopyrroli-din-1-yl)ethyl)amino)-6-(2,6-dichloro- 3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 631 556

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((2-(3-(dimethyl- amino)pyrrolidin-1-yl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydro-2H-pyran-4- yl)acrylamide659 557

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxypehnyl)-8-((2-(2-(dimethyl- amino)ethoxy)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 634 558

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(2-(hydroxy-methyl)pyrrolidin-1-yl)butyl)amino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide674 559

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((4-(3,3-difluoro-pyrrolidin-1-yl)butyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 680 560

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-((4-(3-methoxy-pyrrolidin-1-yl)butyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 674 561

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-methoxypyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 534 562

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-ethoxypyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 548 563

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-isopropoxypyrdo[3,4- d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 562 564

N-((3S,4S)-3-((8-(cyclopropylmeth- oxy)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydro-2H-pyran-4-yl)acryl- amide 574 565

N-((3S,4R)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)-1-methylpyrrolidin- 3-yl)acrylamide 503 566

N-((3S,4R)-1-acetyl-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyrrolidin- 3-yl)acrylamide 531 567

N-((3S,4R)-1-acetyl-4-((6-(2,6-dichloro- 3,5-dimethoxyphenyl)-8-(methyl-amino)pyrido[3,4-d]pyrimidin-2-yl)a- mino)pyrrolidin-3-yl)acrylamide 560568

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)-1-(2-(dimethyl-amino)ethyl)pyrrolidin-3-yl)acrylamide 560 569

(3S,4R)-3-acrylamido-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)pyrido[3,4- d]pyrimidin-2-yl)amino)-N-meth-ylpyrrolidine-1-carboxamide 546 570

N-((3S,4R)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-methylpyrrolidin- 3-yl)acrylamide 572 571

(3S,4R)-3-acrylamido-4-((8-((cyclo- propylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]py- rimidin-2-yl)amino)-N-methyl-pyrrolidine-1-carboxamide 615 572

N-((3S,4R)-1-acetyl-4-((8-((cyclo- propylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d] pyrimidin-2-yl)amino)pyrrolidin-3-yl)acrylamide 600 573

N-((3S,4R)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(oxetan-3-yl)pyrrolidin- 3-yl)acrylamide 614 574

N-((3S,4R)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(2-(dimethylamino)eth- yl)pyrrolidin-3-yl)acrylamide 629575

N-((3S,4R)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(1H-pyrazol-4-yl)pyrroli- din-3-yl)acrylamide 624 576

N-((3S,4R)-4-((8-((cyclopropylmeth-yl)amino)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(1-methyl-1H-pyrazol- 4-yl)pyrrolidin-3-yl)acrylamide 638577

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)-1-methyl- pyrrolidin-3-yl)acrylamide 602 578

(3S,4R)-3-acrylamido-4-((6-(2,6-di-chloro-3,5-dimethoxphenyl)-8-(((tetra-hydrofuran-2-yl)methyl)amino)pyri- do[3,4-d]pyrimidin-2-yl)amino)-N-methylpyrrolidine-1-carboxamide 645 579

N-((3S,4R)-1-acetyl-4-(((6-(2,6-di-chloro-3,5-dimethoxyphenyl)-8-(((tetra-hydrofuran-2-yl)methyl)amino)pyri-do[3,4-d]pyrimidin-2-yl)amino)pyrroli- din-3-yl)acrylamide 630 580

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(((tetrahydrofuran-2-yl)methyl)amino)pyrido[3,4-d]py- rimidin-2-yl)amino)-1-(oxetan-3-yl)pyrrolidin-3-yl)acrylamide 644 581

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran-2-yl)methyl)amino)pyrido[3,4-d]pyrimi- din-2-yl)amino)-1-(2-(dimethyl-amino)ethyl)pyrrolidin-3-yl)acrylamide 659 582

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)-1-(1H-pyrazol- 4-yl)pyrrolidin-3-yl)acrylamide 654583

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((tetrahydrofuran- 2-yl)methyl)amino)pyrido[3,4-d]py-rimidin-2-yl)amino)-1-(1-methyl-1H- pyrazol-4-yl)pyrrolidin-3-yl)acryl-amide 668 584

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(oxetan-3-ylamino)py- rido[3,4-d]pyrimidin-2-yl)amino)-1-methylpyrrolidin-3-yl)acrylamide 574 585

(3S,4R)-3-acrylamido-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)-8-(oxetan- 3-ylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-N-methylpyrrolidine- 1-carboxamide 617 586

N-((3S,4R)-1-acetyl-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)-8-(oxetan-3-ylamino)pyrido[3,4-d]pyrimidin-2-yl) amino)pyrrolidin-3-yl)acrylamide602 587

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(oxetan-3-yl-amino)pyrido[3,4-d]pyrimidin-2-yl)ami- no)-1-(oxetan-3-yl)pyrrolidin-3-yl)acrylamide 616 588

N-((3S,4R)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(oxetan-3-yl-amino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)-1-(2-dimethylamino)ethyl)pyrroli- din-3-yl)acrylamide 631 589

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(oxetan-3-yl-amino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)-1-(1H-pyrazol-4-yl)pyrrolidin- 3-yl)acrylamide 626 590

N-((3S,4R)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(oxetan-3-yl-amino)pyrido[3,4-d]pyrimidin-2-yl)ami- no)-1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)acrylamide 640 591

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-methylpyrrolidin- 3-yl)acrylamide 588 592

(3S,4R)-3-acrylamido-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)-8-((tetra- hydrofuran-3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-N-methyl- pyrrolidine-1-carboxamide 631 593

N-((3S,4R)-1-acetyl-4-((6-(2,6-di-chloro-3,5-dimethoxyphenyl)-8-((tetra-hydrofuran-3-yl)amino)pyrido[3,4-d]py- rimidin-2-yl)amino)pyrrolidin-3-yl)acrylamide 616 594

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(oxetan-3- yl)pyrrolidine-3-yl)acrylamide 630 595

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(2-(dimethylamino)eth- yl)pyrrolidin-3-yl)acrylamide 645596

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(1H-pyrazol-4- yl)pyrrolidine-3-yl)acrylamide 640 597

N-((3S,4R)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((tetrahydrofuran- 3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-1-(1-methyl-1H-pyrazol- 4-yl)pyrrolidin-3-yl)acrylamide 654598

N-((3R,4S)-4-((8-(((R)-1-cyclopropopyl-ethyl)amino)-6-(2,6-dichloro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 573 599

N-((3R,4S)-4-((8-(((R)-1-cylopropyl-ethyl)amino)-6-(2,6-difluoro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 541 600

N-((3R,4S)-4-((8-(((S)-1-cyclopropyl-ethyl)amino)-6-(2,6-dichloro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 573 601

N-((3R,4S)-4-((8-(((S)-1-cyclopropyl-ethyl)amino)-6-(2,6-difluoro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 541 602

N-((3R,4S)-4-((6-(26-dichloro-3,5-di- methoxyphenyl)-8-(((R)-3,3-dimeth-ylbutan-2-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 589 603

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((R)-3,3-dimeth-ylbutan-2-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 557 604

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((S)-3,3-dimeth-ylbutan-2-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 589 605

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(((S)-3,3-dimeth-ylbutan-2-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 557 606

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-methylpyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 504 607

N-((3R,4)S-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-ethylpyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 518 608

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-isopropylpyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 532 609

N-((3R,4S)-4-((8-cyclopropyl-6-(2,6- dichloro-3,5-dimethoxyphenyl)pyri-do[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 530 610

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-neopentylpyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 560 611

N-((3R,4S)-4-((8-(cyclopropylmeth-yl)-6-(2,6-dichloro-3,5-dimethoxyphen-yl)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide544 612

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3-yl)acrylamide 574 613

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((tetrahydrofuran- 2-yl)methyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 574 614

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 574 615

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylpyrroli- din-3-yl)methyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 587 616

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-((1-methylpyrroli- din-2-yl)methyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3-yl) acrylamide 587 617

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide587 618

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(methoxymethyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 534619

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(2-methoxyethyl)pyrido[3,4-d]pyrimidin-2-yl)amino) tetrahydrofuran-3-yl)acrylamide 548620

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(2-(isopropylami-no)ethyl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 575 621

N-((3R,4S)-4-((8-((cyclopropyl- amino)methyl)-6-(2,6-dichloro-3,5-dimeth- oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 559 622

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(methylsulfon-amidomethyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 597 623

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(((1-methylethyl)sul- fonamido)methyl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 625 624

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(2,2,2-trifluoroeth-yl)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide572 625

N-((3R,4S)-4-((8-benzyl-6-(2,6-di-chloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 580 626

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-phenylpyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 566 627

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(pyridin-4-yl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 567628

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxyphenyl)-8-(pyridin-3-yl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 567629

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 570 630

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((1-methyl-1H-pyrazol-4-yl)methyl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 584 631

N-((3R,4S)-4-((8-(1-cyclopropyl-1H-pyrazol-4-yl)-6-(2,6-dichloro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 596 632

N-((3R,4S)-4-((8-(1-(cyclopropyl-methyl)-1H-pyrazol-4-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 610 633

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(1-(2-methoxyeth-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 614 634

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl)pyrido[3,4-d]py- rimidin-2-yl)amio)tetrahydro-furan-3-yl)acrylamide 600 635

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di-methoxphenyl)-8-(1-(tetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 626 636

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-phenethylpyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 594 637

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1-methyl-1H-py-razol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 538 638

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1-(2-methoxy-ethyl)-1H-pyrazol-4-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydr-furan-3-yl)acrylamide 582 639

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-(1-(2-hydroxyeth- yl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 568 640

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- methoxyphenyl)-8-ethylpyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 532 641

N-((3S,4S)-3-((8-(cyclopropylmeth- yl)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydro-2H-pyran-4-yl)acrylamide 558 642

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 588 643

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 588 644

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl) acrylamide 584 645

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((1-methyl-1H-pyrazol-4-yl)methyl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 598 646

N-((3S,4S)-3-((8-(1-cyclopropyl-1H-pyrazol-4-yl)-6-(2,6-dichloro-3,5-di- methoxyphenyl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 610 647

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(1-(2-methoxy-ethyl)-1H-pyrazol-4-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 628 648

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(2-(isopropyl-amino)ethyl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 589 649

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-ethylpyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 500 650

N-((3S,4S)-3-((8-(cyclopropylmeth- yl)-6-(2,6-difluoro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 526 651

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-((tetrahydrofuran- 3-yl)methyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 556 652

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 556 653

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxypehnyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 552 654

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1-(2-methoxy-ethyl)-1H-pyrazol-4-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 596 655

N-((3R,4S)-4-((8-(cyclopropylamino)- 6-(2,6-dichloro-3,5-dimethoxyphen-yl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3- yl)acrylamide545 656

N-((3R,4S)-4-((8-(cyclopropylamino)- 6-(2,6-difluoro-3,5-dimethoxyphen-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3- yl)acrylamide513 657

N-((3R,4S)-4-((8-(azetidin-1-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 545658

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxyazeti-din-1-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3-yl)acryl-amide 575 659

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxyazeti-din-1-yl)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydrofuran-3-yl)acryl-amide 543 660

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-(dimethylami-no)azetidin-1-yl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 588 661

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(3-(trifluorometh-yl)azetidin-1-yl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 613 662

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3,3-dimethylaze-tidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 573 663

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3,3-difluoroaze-tidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 581 664

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(3-hydroxy-3-meth-ylazetidin-1-yl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 575 665

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 589 666

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyri-midin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 557 667

N-((3R,4S)-4-((8-(3-cyano-3-methyl-azetidin-1-yl)-6-(2,6-dichloro-3,5-di-methoxyphenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 584 668

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(2-oxa-6-aza-spiro[3.3]heptan-6-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 587 669

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(2-oxa-6-aza-spiro[3.3]heptan-6-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 555 670

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(1-oxa-6-aza-spiro[3.3]heptan-6-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 587 671

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1-oxa-6-aza-spiro[3.3]heptan-6-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 555 672

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(2-azaspiro[3.3]heptan-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 585 673

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 599 674

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 601 675

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(7-oxa-2-azaspiro[3.5]nonan-2- yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 615 676

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydrofuran-3-yl)acrylamide559 677

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxypyrro-lidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 589 678

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-(3-methoxypyrro-lidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 557 679

N-((3R,4S)-4-((8-(3-cyanopyrrolidin-1-yl)-6-(2,6-dichloro-3,5-dimethoxy-phenyl)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydrofuran-3-yl)acryl-amide 584 680

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3,3-difluoro-pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 595 681

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py-rimidn-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 603 682

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 571 683

N-((3R,4S)-4-((8-(3-cyano-3-methyl-pyrrolidin-1-yl)-6-(2,6-dichloro-3,5- dimethoxyphenyl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 598 684

N-((3R,4S)-4-((8-(3-aza- bicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichloro-3,5-dimethoxyphen- yl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 571 685

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 615 686

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-morpholino-pyrido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 575687

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-morpholino-pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydrofuran-3-yl)acrylamide 543688

N-((3R,4S)-4-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(2-methyl-morpholino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 589 689

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-(2-methyl-morpholino)pyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 557 690

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(2,6-dimethyl-morpholino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 603 691

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(2,6-dimethyl-morpholino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 571 692

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-hydroxypiperi-din-1-yl)pyrido[3,4-d]pyrimidin-2-yl)a- mino)tetrahydrofuran-3-yl)acryl-amide 589 693

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-methoxy-piperidin-1-l)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 603 694

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(4-methoxypiper-idin-1-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydrofuran-3-yl)acryl-amide 571 695

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxy-piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 603 696

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 603 697

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 617 698

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-di- methoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 585 699

N-((3R,4S)-4-((8-(4-cyano-4-methyl-piperidin-1-yl)-6-(2,6-dichloro-3,5-di-methoxyphenyl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofurna-3-yl)acrylamide 612 700

N-(2-(((3S,4R)-4-acrylamidotetrahy-drofuran-3-yl)amino)-6-(2,6-dichloro- 3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-4-8-yl)cyclopropanecarbox- amide 573 701

N-(2-(((3S,4R)-4-acrylamidotetra-hydrofuran-3-yl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]py- rimidin-8-yl)tetrahydrofuran-2-carboxamide 603 702

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(methylsulfonami-do)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide583 703

N-((3S,4S)-3-((8-(cyclopropylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide559 704

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(3-methoxyazeti-din-1-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 589 705

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(3,3-difluoro-azetidin-1-yl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 595 706

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 603 707

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(2-oxa-6-aza-spiro[3.3]heptan-6-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 601 708

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 615 709

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)py- rido[3.4-d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 629 710

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxy-pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4- yl)acrylamide 603 711

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 617 712

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-di- methoxyphenyl)-8-(2,6-dimethyl-morpholino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 617 713

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-hydroxy-4-methylpiperidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 617 714

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(4-methoxy-4-methylpiperidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 631 753

N-((3R,4S)-4-((8-chloro-6-(2,6-di- chloro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro- furan-3-yl)acrylamide 524754

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- bis(methoxy-d₃)phenyl)-8-ethoxy-pyrido[3,4-d]pyrimidin-2- yl)amino)tetra- hydrofuran-3-yl)acrylamide 540755

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((3,5-dimethoxy-benzyl)oxy)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydrofuran-3-yl)acrylamide 656 756

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3,6-dihydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acryl- amide 572 758

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxypehnyl)-8-((3-hydroxy-2,2-bis(hydroxymethyl)propyl)amino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 623759

N-((3R,4S)-4-((8-(3,3-bis(hydroxy-methyl)azetidin-1-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 605 760

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetarhydrofuran-3- yl)acrylamide 589 761

N-((3R,4S)-4-((6-(2-chloro-3,5-dimeth-oxyphenyl)-8-(1-methyl-1H-pyrazol- 4-yl)pyrido[3,4-d]pyrimidin-2-yl)ami-no)tetrahydrofuran-3-yl)acrylamide 536 762

N-((3R,4S)-4-((8-(6-oxa-3-aza- bicyclo[3.1.1]heptan-3-yl)-6-(2,6-di-chloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 587 763

N-((3R,4S)-4-((8-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 587 764

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(methylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 487765

N-((3R,4S)-4-((8-amino-6-(2,6-di- chloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 505 766

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- bis(methoxy-d3)phenyl)-8-((methyl-d3)amino)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydrofuran-3-yl)acrylamide 528 767

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(ethylamino)pyri-do[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 501 768

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3,3-difluoro-azetidin-1-yl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 549 769

N-((3R,4S)-4-((8-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)-6-(2,6-difluoro-3,5-dimethoxy- phenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 555 770

N-((3R,4S)-4-((6-(2-fluoro-3-meth- oxyphenyl)-8-(methylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- furan-3-yl)acrylamide 439 771

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((methyl-d₃)ami-no)pyrido[3,4-d]pyrimidin-2-yl)ami- no)tetrahydrofuran-3-yl)acrylamide522 772

N-((3R,4S)-4-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py-rimidin-2-l)amino)tetrahydrofuran-3- yl)acrylamide 557 773

N-((3R,4S)-4-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-hydroxy-3-meth- ylazetidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran-3- yl)acrylamide 543 774

N-((3R,4S)-4-((8-(azetidin-1-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)amino)tetra-hydrofuran-3-yl)acrylamide 513 775

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxyazeti-din-1-yl)pyrido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydro-2H-pyran-4-yl)acryl- amide 557 776

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimi- din-2-yl)amino)tetrahydrofuran-3-yl)acrylamide 615 777

N-((3R,4S)-4-((6-(2,6-difluoro-3-meth- oxyphenyl)-8-(methylamino)pyri-do[3,4-d]pyrimidin-2-yl)amino)tetra- hydrofuran-3-yl)acrylamide 457 778

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((S)-3-hydroxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydrofuran- 3-yl)acrylamide 589 779

N-((3R,4S)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-((R)-3-hydroxy-3-methylpyrrolidin-1-yl)pyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-furan-3-yl)acrylamide 589 780

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-morpholino-pyrido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide589 781

N-((3S,4S)-3-((8-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)-6-(2,6-dichloro-3,5-dimethoxy- phenyl)pyrido[3,4-d]py-rimidin-2-yl)amino)tetrahydro-2H- pyran-4-yl)acrylamide 601 782

N-((3S,4S)-3-((8-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydro-2H-pyran- 4-yl)acrylamide 601 783

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 603 784

N-((3S,4S)-3-((8-(azetidin-1-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 559 785

N-((3S,4S)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-8-(3-hydroxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 589 786

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(methylamino)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide501 787

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(ethylamino)pyri-do[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide 515788

N-((3S,4S)-3-((8-(cyclopropylamino)-6-(2,6-difluoro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide527 789

N-((3S,4)S-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-morpholinopy-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide557 790

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 571 791

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3,3-difluoroazet-idin-1-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 563 792

N-((3S,4S)-3-((8-(azetidin-1-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 527 793

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-hydroxy-3-methylazetidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 557 794

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(3-methoxy-pyrrolidin-1-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 571 795

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(4-methoxy-piperidin-1-yl)pyrido[3,4-d]pyrimidin- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 585 796

N-((3S,4S)-3-((8-(6-oxa-3-aza- bicyclo[3.1.1]heptan-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)py- rido[3,4-d]pyrimidin-2-yl)a-mino)tetrahydro-2H-pyran-4- yl)acrylamide 569 797

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-((2,2,2-trifluoro-ethyl)amino)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 569 798

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-((3,3-dimethyl-butan-2-yl)amino)pyrido[3,4-d]pyrimi-din-2-yl)amino)tetrahydro-2H-pyran- 4-yl)acrylamide 571 799

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-methoxypyrido[3,4- d]pyrimidin-2-yl)amino)tetra-hydro-2H-pyran-4-yl)acrylamide 502 800

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-methylpyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 486 801

N-((3S,4)S-3-((8-cyclopropyl-6-(2,6- difluoro-3,5-dimethoxyphenyl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide512 802

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(piperidin-4-yl)py-rido[3,4-d]pyrimidin-2-yl)amino)tetra- hydro-2H-pyran-4-yl)acrylamide555 803

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2- yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 538 804

N-((3S,4S)-3-((6-(2,6-difluoro-3,5- dimethoxyphenyl)-8-(1-(2-hydroxyeth-yl)-1H-pyrazol-4-yl)pyrido[3,4-d]py- rimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 582 805

N-((3S,4S)-3-((6-(2,6-difluoro-3,5-di-methoxyphenyl)-8-phenylpyrido[3,4- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide 548 806

N-((3S,4S)-3-((8-chloro-6-(2,6-di-fluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yL)amino)tetrahydro- 2H-pyran-4-yl)acrylamide 506

Example 715 Preparation ofN-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide

Step 1: Preparation of6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(1-(2-methoxyethyl)-4-nitro-1H-pyrazol-5-yl)pyrido[3,4-d]pyrimidine

1-(2-methoxyethyl)-4-nitro-H-pyrazole (84 mg, 0.49 mmol) and2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine(200 mg, 0.54 mmol) were dissolved into DMA (15 mL), then CuI (112 mg,0.59 mmol), PivOH (15 mg, 0.15 mmol), K₂CO₃ (88 mg, 0.64 mmol) andPd(PPh₃)₂Cl₂ (34 mg, 0.05 mmol) were added, the mixture was heated to140° C. under N₂ and stirred for 1 h. The reaction was completed, andthe mixture was concentrated to remove the solvent by reduced pressureand separated by fast silica gel column (PE/EA 2:1) to obtain compound6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(1-(2-methoxyethyl)-4-nitro-1H-pyrazol-5-yl)pyrido[3,4-d]pyrimidine(103 mg, yield 42%). MS m/z (ESI): 505 [M+1]⁺.

Step 2: Preparation of5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazolyl-4-amine

6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(1-(2-methoxyethyl)-4-nitro-1H-pyrazol-5-yl)pyrido[3,4-d]pyrimidine(103 mg, 0.20 mmol) was dissolved in the mixture of EtOH and H₂O (10/3mL), then Fe powder (114 mg, 2.04 mmol) and NH₄Cl (109 mg, 2.04 mmol)were added, the mixture was heated to reflux and stirred for 2 h. Afterthe reaction was completed, the reaction liquid was extracted for threetimes with dichloromethane. The organic phases were combined, washedwith water, then a saturated aqueous sodium chloride solution, driedover anhydrous sodium sulfate, filtrated and concentrated. The crudeproduct was separated by fast silica gel column chromatography(CH₂Cl₂/MeOH 10:1) to obtain compound5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazolyl-4-amine(12 mg, yield 12%). MS m/z (ESI): 476 [M+1]⁺.

Step 3: Preparation ofN-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)1-2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide

5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazolyl-4-amine(12 mg, 0.025 mmol) was dissolved in the mixture of THF and H₂O (4:1, 4mL), then NaHCO₃ (11 mg, 0.13 mmol) was added, the mixture was cooledunder ice water bath, Acryloyl chloride (2.3 mg, 0.025 mmol) as added,and the mixture was stirred at 0° C. for 10 min. After the reaction wascompleted, the reaction liquid w as concentrated by reduced pressure,separated by silica gel column chromatography (CH₂Cl₂/MeOH 10:1) toobtain compoundN-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide(4.8 mg, yield 36%). MS m/z (ESI): 529 [M+1]⁺.

¹H NMR (400 MH-z, CDCl₃) δ 10.71 (s, 1H), 9.63 (s, 1H) 9.60 (s, 1H),8.61 (s, 1H), 7.80 (s, 1H), 6.72 (s, 1H), 6.49 (d, J=16.7 Hz, 1H), 6.40(dd, J=16.9, 9.7 Hz, 1H), 5.84 (d, J=9.7 Hz 1H), 5.21 (t, J=6.0 Hz, 2H),4.00 (s, 7H), 3.89 (t, J=5.9 Hz, 2H), 3.35 (s, 3H).

Examples 716-729 were prepared by referring to the synthesis method ofExample 715.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 716

N-(5-(7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl) acrylamide 544 717

N-(5-(7-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)-1H- pyrazol-4-yl)acrylamide 558718

N-(5-(7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)-6-methyl-5-oxo-5,6-dihydro-2,6- naphthyridin-3-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide 542 719

N-(5-(6-(2-(tert-butylamino)-2-oxoethyl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)-1H-pyazol-4-yl) acrylamide 657 720

N-(5-(6-(cyclopropylmethyl)-7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)acrylamide598 721

N-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazol- 4-yl)acrylamide 545 722

N-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)acrylamide559 723

N-(5-(7-(2,6-dichloro-3,5-dimethoxyphenyl)- 2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide 528 724

N-(5-(7-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridin-3-yl)-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)acrylamide601 725

N-(5-(7-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methoxy-2,6-naphthyridin-3-yl)-1- (2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide 558 726

N-(5-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-oxo-1H-pyrano[4,3-c]pyridin-7-yl)- 1-(2-methoxyethyl)-1H-pyrazol-4-yl)acrylamide 545 727

N-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methoxypyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl) acrylamide 560 728

N-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((2-methoxyethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)acrylamide 602 729

N-(5-(8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)acrylamide598

Example 730 Preparation ofN-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)acrylamide

Step 1: Preparation of3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-carbonitrile

7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one(250.0 mg, 0.626 mmol), Zn(CN)₂ (110 mg, 0.938 mmol) and1,1′-bis(diphenylphosphino)ferrocene (34.7 mg, 0.063 mmol) were added tothe mixture of DMF and H₂O (5 mL, 100:1), then Pd₂(dba)₃ (28.7 mg, 0.031mmol) was added under N₂, the mixture was heated to 12 0° C. and stirredfor 20 h. The reaction was completed, and the mixture was cooled to roomtemperature, diluted with water and extracted with EtOAc. The organicphase was washed with saturated brine, dried over anhydrous sodiumsulfate, filtrated, concentrated and separated by silica gel columnchromatography (Eluent: PE/EtOAc=10-25%) to obtain compound3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-carbonitrile(75 mg, yield: 28%). MS m/z (ESI): 390.0 [M+H]⁺.

Step 2: Preparation of7-(aminomethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one

3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-carbonyl-1,2-dihydro-1,6-naphthyridin-7-carbonitrile(15 mg, 0.038 mmol) was dissolved in methanol (3 mL), and concentratedhydrochloric acid (15 mL) and 10% Pd/C (catalytic amount) were added,the mixture was stirred at room temperature for 2 h under H₂, thereaction was completed. The reaction liquid was filtrated and evaporatedin vacuo to obtain the crude product7-(aminomethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one,which can be directly used in the next reaction. MS m/z (ESI): 394.0[M+H]⁺.

Step 3: Preparation ofN-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)acrylamide

At 0° C., acryloyl chloride (3.8 mg, 0.042 mmol) was added to a solutionof 7-(aminomethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-,6-naphthyridin-2(1H)-one (the crud e product, 0.038 mmol) and NaHCO₃(19.0 mg, 0.230 mmol) in the mixture of THF and H₂O (0.8 mL/0.2 mL), themixture was stirred for 10 min At 0° C. The reaction liquid was dilutedwith EtOAc (5 mL), washed with saturated brine, dried over anhydroussodium sulfate, filtrated, concentrated and separated by a preparativeTLC (Eluent: CH₂Cl₂/MeOH=10:1) to obtain compoundN-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)acrylamide(1.1 mg, two-step yield: 6%).

¹H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.68 (s, 1H), 7.40 (s,1H), 6.65 (s, 1H), 6.38-6.32 (m, 1H), 6.27-6.21 (m, 1H), 5.73-5.69 (m,1H), 5.30 (s, 1H), 4.81 (d, J=5.6 Hz, 2H), 3.96 (s, 6H), 3.78 (s, 3H):

MS m/z (ESI): 448.0 [M+H]⁺.

Examples 731-751 were prepared referring to the synthesis method ofExample 730.

Example MS: m/z No. Compound structure Compound name [M + 1]⁺ 731

N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydro-1,6-naphthyridin-7-yl)methyl)acrylamide 516 732

N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)- 2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydro-1,6-naphthyridin- 7-yl)methyl)acrylamide 504 733

N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)- 1-(2-methoxyethyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl) methyl)acrylamide 492 734

N-((7-(2,6-dichloro-3,5-dimethoxyphenyl)- 2,6-naphthyridin-3-yl)methyl)acrylamide 418 735

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl) pyrido[3,4-d]pyrimidin-2-yl)methyl)acrylamide 419 736

N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)- 1-oxo-1H-pyrano[4,3-c]pyridin-7-yl)methyl)acrylamide 435 737

N-((7-(2,6-dichloro-3,5-dimethoxyphenyl)- 5-oxo-5,6-dihydro-2,6-naphthyridin-3-yl)methyl)acrylamide 434 738

N-((7-(2,6-dichloro-3,5-dimethoxyphenyl)- 6-methyl-5-oxo-5,6-dihydro-2,6-napthyridin-3-yl)methyl) acrylamide 448 739

N-((7-(2,6-dichloro-3,5-dimethoxyphenyl)- 5-methoxy-2,6-naphthyridin-3-yl)methyl)acrylamide 448 740

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-2-yl)methyl) acrylamide 435 741

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-7-methyl-8-oxo-7,8-dihydropyrido [3,4-d]pyrimidin-2-yl)methyl)acrylamide449 742

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-methoxypyrido[3,4-d]pyrimidin-2-yl)methyl)acrylamide 449 743

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl) thieno[2,3-d]pyrimidin-2-yl)methyl)acrylamide 424 744

N-((2-(2,6-dichloro-3,5-dimethoxyphenyl) thiazolo[5,4-d]pyrimidin-5-yl)methyl)acrylamide 425 745

N-((2-(2,6-dichloro-3,5-dimethoxyphenyl) thiazolo[4,5-c]pyridin-6-yl)methyl)acrylamide 424 746

N-((2-(2,6-dichloro-3,5-dimethoxyphenyl)- 4-oxo-4H-pyrano[2,3-c]pyridin-6-yl)methyl)acrylamide 435 747

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-oxo-8H-pyrano[3,2-d]pyrimidin-2-yl)methyl)acrylamide 436 748

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-oxo-5,8-dihydropyrido[3,2-d]pyrimidin-2-yl)methyl) acrylamide 435 749

N-((6-(2,6-dichloro-3,5-dimethoxyphenyl)- 8-((2-methoxyethyl)amino)pyrido[3,4-d]pyrimidin-2-yl) methyl)acrylamide 492 750

N-((8-((cyclopropylmethyl)amino)- 6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl) methyl)acrylamide 488 751

N-((7-(2,6-dichloro-3,5-dimethoxyphenyl)- 5-((2-methoxyethyl)amino)-2,6-naphthyridin-3-yl)methyl) acrylamide 491

Biological Test and Evaluation

I. In Vitro Biochemical Kinase Analysis of FGFR4

FGFR4 Caliper Assay was used in the present invention to determine theinhibitory activities of the compounds against FGFR4. The detailedexperimental procedure was as follows.

1. The kinase reaction in the present invention was carried out in a384-well plate, and 12.5 μM of FGFR4, 65 μM of ATP and 1 μM of peptide(5 Fluo Ahx KKKKEEIYFFFG NH2) were respectively added into the followingreaction system.

2. A reaction system is a mixture solution of 50 mM HEPES, pH 7.5, 1 mMDTT, 0.02% Tween 20, 0.02% BSA, 0.6% DMSO, 10 mM beta glycerol phosphateand 10 μM sodium orthovanadate and 16 mM MgCl₂.

3. The reaction system was incubated at 30° C. for 40 minutes.

4. The reaction was terminated by adding a stop solution (100 mM HEPES,pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA and 0.015%Brij35).

5. The culture plate with the terminated kinase reaction was transferredto the Caliper LC 3000 workstation to read the data, the phosphorylatedand unphosphorylated peptides were separated by using the Calipermicrofluid migration shift technique, and the analyte was transferred byallowing a constant buffer flow through the chip, the migration of thesubstrate peptide was monitored by the labeled fluorescent signal, andthe kinase activity was calculated by using the amount of thephosphate-based peptide formed.

6. Finally, IC₅₀ values were determined by non-linear regressionanalysis of percent inhibition at different compound concentrations. Thetest results for the enzymatic activities of the compounds of thespecific examples were shown in Table 1.

II. FGFR4 Cell Proliferation Experiment

Cell Titer Glo (CTG) experiment was used in the present invention toevaluate the functional effects of the compounds on cell proliferation.Huh7 hepatocellular carcinoma cells (Catalog No. TChU182) from theChinese Academy of Sciences cell bank were cultured in DMEM with highglucose (Gibco, cat. No. 1773536), 10% fetal bovine serum (Gibco,10099-141) at 37° C., in a 5% CO₂ incubator. Compound-mediatedinhibition of cell proliferation/survival was assessed by quantificationof cellular ATP levels using CTG reagent (Promega, #G7573). The specificexperimental procedure was as follows:

1. The cells were seeded into a tissue culture medium-treated 96-wellplate (Costar #3904) at 3500 cells/well/90 μL of fresh medium:

2. 10 μL of medium containing a compound concentration of 10 fold of itsfinal test concentration was added;

3. The dose effect was evaluated by a 5-fold serial dilution of the testcompound, starting from 10 μM.

4. After cells incubation for 3 days at 37° C. under 5% CO₂, the effectof the inhibitor on cell proliferation was quantified after adding 50 μLof CTG and testing with luminescence.

5. The concentration of the compound (EC₅₀) leading to half maximalgrowth inhibition and the concentration of compound (Absolute IC₅₀)leading to absolute half growth inhibition were determined using afour-parameter curve fit in Graphpad Prism in a plate reader (M1000,Tecan). The test results of cell activities for the compounds ofspecific examples were shown in Table 1.

TABLE 1 The results of enzymatic activity and cell activity testsEnzymatic Cell activity activity HuH-7 Example FGFR4 HuH-7 Absolute No.IC₅₀ (nM) EC₅₀ (nM) IC₅₀ (nM) ¹H-NMR Example 1 13.9 1527 2446 ¹H NMR(400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H),7.10-7.05 (m, 2H), 6.68 (s, 1H), 6.52-6.48 (m, 1H), 6.44 (s, 1H), 6.39(s, 1H), 6.33 (d, J = 1.4 Hz, 1H), 6.19 (d, J = 10.2 Hz, 1H), 5.68 (dd,J = 10.2, 1.4 Hz, 1H), 3.99 (s, 6H), 3.25 (s, 3H), 2.21 (s, 3H). Example5 26.1 >10000 >10000 ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 8.72 (s,1H), 8.23 (s, 3H), 7.34 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H),7.02 (s, 1H), 6.70 (s, 1H), 6.42-6.25 (m, 2H), 5.71 (d, J = 9.8 Hz, 1H),3.97 (s, 6H), 2.25 (s, 3H). Example 7 28.9 >10000 >10000 ¹H NMR (400MHz, CDCl₃) δ 8.53 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 6.67 (s,1H), 6.54 (s, 1H), 6.39 (d, J = 16.7 Hz, 1H), 6.25-6.13 (m, 1H), 5.73(d, J = 10.0 Hz, 1H), 3.96 (s, 6H), 2.22 (s, 3H). Example 9 138 89 1049¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.34(t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.65 (s,2H), 6.35 (d, J = 15.3 Hz, 2H), 6.16 (dd, J = 17.2, 9.9 Hz, 1H), 5.68(d, J = 10.2 Hz, 1H), 3.97 (s, 9H), 2.23 (s, 3H). Example 105.3 35154817 ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.38 (d, J = 8.2  10 Hz,1H), 8.17 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H),6.98 (s, 1H), 6.64 (s, 1H), 6.56 (s, 1H), 6.37 (d, J = 16.8 Hz, 1H),6.20 (dd, J = 16.9, 10.2 Hz, 1H), 5.70 (d, J = 10.2 Hz, 1H), 4.07 (s,3H), 3.96 (s, 6H), 2.25 (s, 3H). Example 100.7 4717 4717 ¹H NMR (400MHz, CDCl₃) δ 8.76 (s, 1H), 8.27 (d, J = 8.2  11 Hz, 1H), 8.14 (s, 1H),7.49 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H) 6.94(s, 1H), 6.69 (s, 1H), 6.43- 6.34 (m, 1H), 6.26 (dd, J = 16.9, 10.1 Hz,1H), 5.72 (dd, J = 10.1, 1.4 Hz, 1H), 3.98 (s, 6H), 3.51 (t, J = 6.4 Hz,2H), 3.22 (s, 3H), 2.24 (s, 3H), 1.27 (d, J = 7.0 Hz, 2H). Example 43.83352 3352 ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 8.02 (s, 1H),  12 7.57(s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.64 (s,1H), 6.41 (d, J = 16.6 Hz, 1H), 6.26 (dd, J = 16.6, 9.8 Hz, 1H), 6.07(s, 1H), 5.74 (d, J = 9.8 Hz, 1H), 3.95 (s, 6H), 2.08 (s, 3H). Example8.0 181.5 513.1 ¹H NMR (400 MHz, Methanol-d₄) δ 9.05 (s, 1H), 8.98  13(s, 1H), 7.72 (s, 1H), 7.68-7.66 (d, J = 8.0 Hz, 1H), 7.32-7.24 (m, 2H),6.91 (s, 1H), 6.47(s, 1H), 6.35-6.23 (m, 2H), 5.66-5.63 (dd, J = 8 Hz,1H), 3.97(s, 6H), 2.30(s, 3H). Example 53.3 54.2 268.5 ¹H NMR (400 MHz,CDCl₃) δ 10.72 (s, 1H), 9.31-9.24  64 (m, 2H), 8.24 (s, 1H), 7.64 (s,1H), 6.70 (s, 1H), 6.42- 6.33 (m, 2H), 5.75 (dd, J = 9.0, 2.6 Hz, 1H),5.38-5.32 (m, 1H), 3.99 (s, 6H), 3.87 (s, 3H). Example246.6 >10000 >10000 ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.08 (s,1H),  75 7.97 (s, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.54-6.50 (m, 1H), 6.28 (d, J = 16.6 Hz, 1H), 6.13-6.03 (m, 1H), 5.70-5.57(m, 1H), 3.91 (s, 61H), 3.49-3.38 (m, 4H), 3.25 (s, 3H), 2.54-2.39 (m,4H), 2.08 (s, 3H), 1.31 (s, 3H). Example 24.0 23.8 62.6 ¹H NMR (400 MHz,CDCl₃) δ 9.03 (s, 1H), 8.17 (s, 1H)  76 6.77 (s, 1H), 6.63 (s, 1H), 6.38(d, J = 16.6 Hz, 2H), 6.33- 6.24 (m, 1H), 5.70 (d, J = 10.1 Hz, 1H),3.95 (s, 6H), 3.87 (s, 3H), 3.53-3.36 (m, 2H), 1.19-1.10 (m, 1H),0.55-0.41(m, 2H), 0.42-0.29 (m, 2H). Example 80.5 179.4 332.8 ¹H NMR(400 MHz, CDCl₃) δ 9.21 (s, 1H), 9.16 (s, 1H), 118 7.55 (s, 1H), 6.68(s, 1H), 6.45 (d, J = 7.3 Hz, 1H), 6.27 (dd, J = 17.0, 1.4 Hz, 1H), 6.07(dd, J = 16.9, 10.3 Hz, 1H), 5.63 (dd, J = 10.2, 1.4 Hz, 1H), 4.94 (dd,J = 11.6, 4.9 Hz, 1H), 4.90-4.79 (m, 1H), 4.34-4.19 (m, 2H), 3.98 (s,6H), 3.90-3.79 (m, 2H). Example 166.0 78.1 457.1 ¹H NMR (400 MHz, CDCl₃)δ 9.17 (s, 2H), 7.56 (s, 1H), 119 6.68 (s, 1H), 6.25 (dd, J = 16.9, 1.4Hz, 1H), 6.01 (dd, J = 17.0, 10.3 Hz, 1H), 5.60 (dd, J = 10.3, 1.4 Hz,1H), 4.55 (s, 1H), 4.35 (s, 1H), 4.11-4.00 (m, 2H), 3.98 (s, 6H), 3.78(d, J = 12.1 Hz, 1H), 3.64 (dd, J = 3.4, 10.9 Hz, 1H), 2.24-2.20 (m,2H), 2.02-1.99 (m, 2H). Example 303.0 155.6 754.2 1H NMR (400 MHz,CDCl₃) δ 9.20 (s, 1H), 9.14 (s, 1H), 120 7.71 (s, 1H), 6.73 (t, J = 8.0Hz, 1H), 6.46 (d, J = 7.0 Hz, 1H), 6.26 (d, J = 16.9 Hz, 2H), 6.04 (dd,J = 17.0, 10.3 Hz, 1H), 5.62 (d, J = 10.2 Hz, 1H), 4.93 (d, J = 6.0 Hz,1H), 4.86 (t, J = 6.2 Hz, 1H), 4.28 (ddd, J = 18.7, 9.4, 6.2 Hz, 2H),3.93 (s, 6H), 3.85 (ddd, J = 15.4, 9.5, 4.9 Hz, 2H). Example 182.6 171.9401.4 ¹H NMR (400 MHz, CDCl₃) δ 9.20 (d, J = 9.2 Hz, 2H), 121 7.94 (s,1H), 6.82 (d, J = 2.8 Hz, 1H), 6.60 (d = 2.7 Hz, 1H), 6.48-6.43 (m, 1H),6.24 (t, J = 1.9 Hz, 1H), 6.18 (dd, J = 17.3, 10.4 Hz, 1H), 6.12-6.04(m, 1H), 5.63 (dt, J = 10.3, 1.6 Hz, 1H), 4.97-4.85 (m, 3H), 4.28 (ddd,J = 20.2, 9.5, 6.3 Hz, 3H), 3.98 (s, 3H), 3.94 (s, 3H). Example 61.6302.7 556 ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 9.02 (s, 124 1H),8.11-8.09 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.03 (s, 1H), 6.92 (s, 1H),6.70-6.68 (dd, J = 8 Hz, 1H), 6.23-6.16 (dd, J = 16 Hz, 1H), 6.01-5.97(dd, J = 16 Hz, 1H), 5.52-5.48 (dd, J = 16 Hz, 1H), 4.75-4.68 (m, 1H),4.59-4.52 (m, 1H), 4.15-4.11 (m, 1H), 4.06-4.03 (m, 1H), 3.98 (s, 6H),3.74-3.67 (m, 2H). Example 22.0 31.5 53.7 ¹H NMR (400 MHz, CDCl₃) δ8.68(s, 1H), 6.82 (s, 1H), 126 6.76 (s, 1H), 6.62(s, 1H), 6.44 (s, 1H),6.22-6.18 (dd, J = 16 Hz, 1H), 6.00-5.94 (dd, J = 16 Hz, 1H),5.55-5.52(dd, J = 8 Hz, 1H), 4.92-4.85 (m, 1H), 4.56-4.50 (m, 1H),4.30-4.21 (m, 2H), 3.98 (s, 6H), 3.87-3.84 (dd, J = 12 Hz, 1H),3.77-3.74 (dd, J = 12 Hz, 1H), 4.42-4.39 (m, 2H), 1.23-1.19 (m, 1H),0.59-0.53 (m, 2H), 0.33-0.29 (m, 2H), Example 12.4 5.4 10.0 ¹H NMR (400MHz, CDCl₃) δ 8.89 (s, 1H), 6.80 (brs, 1H), 421 6.68 (s, 1H), 6.62 (s,1H), 6.38 (brs, 1H), 6.21 (dd, J = 17.0, 1.5 Hz, 1H), 6.02 (dd, J =17.0, 10.2 Hz, 1H),, 5.56 (dd, J = 10.1, 1.5 Hz, 1H), 4.93-4.83 (m, 2H),4.30- 4.18(m, 2H), 3.96 (s, 6H), 3.90 (dd, J = 9.7, 3.2 Hz, 1H), 3.79(dd, J = 9.2, 5.2 Hz, 1H), 3.52-3.37 (m, 2H), 0.88 (t, J = 6.0 Hz, 1H),0.57-0.48 (m, 2H), 0.36-0.26 (m, 2H). Example 22.5 47.0 238.5 ¹H NMR(400 MHz, CDCl₃) δ 8.92 (s, 1H), 6.74 (s, 1H), 422 6.67 (s, 2H), 6.22(d, J = 15.4 Hz, 1H), 5.56 (d, J = 10.4 Hz, 1H), 4.89 (s, 2H), 4.29-4.17(m, 2H), 3.98 (s, 6H), 3.96-3.80 (m, 4H), 3.76-3.65 (m, 2H), 3.35 (s,3H). Example 31.7 98.0 347.6 ¹H NMR (400 MHz, CDCl₃) δ 9.13 (s, 1H),7.17 (s, 1H), 423 6.75 (s, 1H), 6.66 (s, 1H), 6.26 4 J = 16.9 Hz, 1H),6.12 (dd, J = 17.0, 10.2 Hz, 1H), 5.61 (d, J = 10.2 Hz, 1H), 5.03- 4.93(m, 1H), 4.93-4.85 (m, 1H), 4.31-4.20 (m, 2H), 4.14 (s, 3H), 3.98 (s,6H), 3.88 (dd, J = 9.8, 4.0 Hz, 1H), 3.82 (dd, J = 9.3, 6.5 Hz, 1H).Example 11.0 18.5 37.2 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.85 (s,1H), 424 6.82 (t, J = 8.0 Hz, 1H), 6.15 (dd, J = 17.1, 2.5 Hz, 1H),6.12-6.02 (m, 1H), 5.53 (dd, J = 9.5, 2.5 Hz, 1H), 4.99 (td, J = 6.3,4.8 Hz, 1H), 4.87 (q, J = 6.5 Hz, 1H), 4.27 (dd, J = 9.4, 6.3 Hz, 1H),4.16 (dd, J = 9.0, 6.9 Hz, 1H), 3.92 (m, 7H), 3.80 (dd, J = 9.0, 6.5 Hz,1H), 3.45 (dd, J = 13.7, 7.0 Hz, 1H), 3.37 (d, J = 6.8 Hz, 1H),1.33-1.24 (m, 1H), 0.55-0.41 (m, 2H), 0.42-0.29 (m, 2H). Example 7.7 NTNT ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 6.68 (s, 1H), 425 6.61 (s,1H), 6.22 (d, J = 16.6 Hz, 2H), 6.00 (dd, J = 16.9, 10.2 Hz, 1H), 5.89(s 1H), 5.57 (d, J = 10.2 Hz, 1H), 4.89 (s, 2H), 4.30-4.20 (m, 2H), 3.90(d, J = 9.8 Hz, 1H), 3.82- 3.72 (m, 1H), 3.42 (s, 2H), 1.26-1.21 (m,1H), 0.58- 0.47 (m, 2H), 0.36-0.27 (m, 2H). Example 22.4 63.2 184.5 ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.06 (s, 1H), 429 6.78 (s, 1H),6.64 (s, 1H), 6.18 (d, J = 17.0 Hz, 1H), 6.11 (d, J = 7.2 Hz, 1H), 5.98(dd, J = 17.0, 10.2 Hz, 1H), 5.81 (s, 1H), 5.56 (d, J = 10.3 Hz, 1H),4.94-4.83 (m, 2H), 4.27 (dd, J = 9.6, 5.8 Hz, 1H), 4.20 (dd, J = 9.4,6.1 Hz, 1H), 4.10 (s, 2H), 3.97 (s, 6H), 3.87 (dd, J = 9.6, 3.9 Hz, 1H),3.81 (dd, J = 9.5, 5.0 Hz, 1H), 3.49-3.38 (m, 2H), 3.01 (q, J = 7.5 Hz,2H), 1.27 (t, J = 7.4 Hz, 3H). Example 19.1 32.0 93.5 ¹H NMR (400 MHz,CDCl₃) δ 8.60 (s, 1H), 7.24 (s, 1H), 430 6.81 (brs, 1H), 6.63 (s, 1H),6.57 (s, 1H), 6.26 (brs, 1H), 6.16-6.03 (m, 2H), 5.53 (d, J = 9.6 Hz1H), 5.08 (s, 1H), 4.88 (s, 1H), 4.26-4.12 (m, 2H), 3.96 (d, J = 6.0 Hz,6H), 3.93-3.88 (m, 2H), 3.81 (d, J = 10.1 Hz, 2H), 3.60 (d, J = 11.3 Hz,2H), 3.42 (s, 1H), 2.94 (s, 3H). Example 519.1 NT NT ¹H NMR (400 MHz,CDCl₃) δ 12.21 (s, 1H), 8.90 (s, 1H), 431 7.72 (s, 1H), 7.52 (s, 1H),6.78 (s, 1H), 6.67 (s, 1H), 6.22- 6.12 (m, 2H), 5.53 (d, J = 9.9 Hz,1H), 5.00-4.88 (m, 2H), 4.33-4.27 (m, 2H), 4.26-4.19(m, 2H), 3.97 (s,6H), 3.94-3.87 (m, 2H), 3.49 (s, 2H), 2.87 (s, 6H). Example 105.8 395.8934.2 ¹H NMR (400 MHz, CDCl₃) δ8.66 (s, 1H), 6.99 (s, 1H), 432 6.91 (s,1H), 6.63 (s, 1H), 6.59 (s, 1H), 6.33 (d, J = 6.4 Hz, 1H), 6.18 (d, J =5.9 Hz, 2H), 5.59-5.49 (m, 1H), 4.99 (s, 2H), 4.30-4.23(m, 2H), 3.97 (s,6H), 3.92-3.87 (m, 1H), 3.77-3.71 (m, 1H), 3.25 (s, 2H), 2.77 (s, 6H),2.25 (s, 2H), 1.70 (s, 2H). Example 7.6 19.3 26.1 ¹H NMR (400 MHz,CDCl₃) δ 8.88 (s, 1H), 6.67 (s, 1H), 433 6.62 (s, 1H), 6.30 (brs, 1H),6.19 (d, J = 16.9 Hz, 1H), 5.97 (dd, J = 17.0, 10.3 Hz, 1H), 5.88 (brs,1H), 5.54 (d, J = 10.4 Hz, 1H), 4.95-4.83 (m, 2H), 4.29-4.18 (m, 2H),3.95 (s, 614), 3.89 (dd, J = 9.7, 3.0 Hz, 1H), 3.77 (dd, J = 9.3, 5.5Hz, 1H), 3.14 (d, J = 4.4 Hz, 3H). Example 8.4 9.6 18.2 ¹H NMR (400 MHz,CDCl₃) δ 8.87 (s, 1H), 6.67 (s, 1H), 434 6.62 (s, 1H), 6.51 (s, 1H),6.27-6.15 (m, 2H), 5.97 (dd, J = 16.9, 10.3 Hz, 1H), 5.79 (s, 1H), 5.56(dd, J = 10.3, 1.4 Hz, 1H), 4.97-4.82 (m, 2H), 4.29-4.18 (M, 2H), 3.96(s, 6H), 3.89 (dd, J = 9.6, 3.2 Hz, 1H), 3.76 (dd, J = 9.2, 5.5 Hz, 1H),3.65-3.50 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H). Example 67.0 80 148.5 ¹HNMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 6.85 (s, 1H), 435 6.79 (s, 1H),6.64 (s, 1H), 6.19 (d, J = 16.9 Hz, 1H), 6.13 (s, 1H), 6.06 (s, 1H),5.98 (dd, J = 17.0, 10.3 Hz, 1H), 5.56 (d, J = 10.2 Hz, 1H), 4.93 (dd, J= 11.7, 4.8 Hz, 2H), 4.51- 4.37 (m, 1H), 4.30-4.17 (m, 3H), 3.97 (s,6H), 3.90 (dd, J = 9.7, 2.8 Hz, 1H), 3.78 (dd, J = 9.4, 5.0 Hz, 1H).Example >10000 NT NT ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 6.59 (s,1H), 436 6.56 (s, 1H), 6.45 (s, 1H), 6.22 (s, 1H), 6.14-6.00 (m, 1H),5.62 (d, J = 10.2 Hz, 1H), 4.86 (s, 2H), 4.24 (s, 2H), 3.98-3.94 (m,2H), 3.83 (s, 6H), 3.38 (s, 6H). Example 3.5 9.9 17.8 ¹H NMR (400 MHz,CDCl₃) δ 8.89 (s, 1H), 6.84 (brs, 1H), 438A 6.70 (s, 1H), 6.63 (s, 1H),6.42 (brs, 1H), 6.22 (dd, J = 17.0, 1.5 Hz, 1H), 6.11-6.01 (m, 1H), 5.85(s, 1H), 5.57 (dd, J = 10.1, 1.5 Hz, 1H), 4.93-4.81 (m, 2H), 4.30-4.16(m, 3H), 3.96 (s, 6H), 3.92-3.82 (m, 3H), 3.82-3.74 (m, 2H), 3.58-3.45(m, 1H), 1.95-1.85 (m, 2H), 1.70-1.64 (m, 2H). Example 9.1 15.8 35.1 ¹HNMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.74 (s, 1H), 438B 6.69 (s, 1H),6.62 (s, 1H), 6.25 (dd, J = 16.9, 1.4 Hz, 1H), 6.20 (s, 1H), 6.03 (dd, J= 16.9, 10.3 Hz, 1H), 5.81 (s, 1H), 5.61 (d, J = 10.4 Hz, 1H), 4.93-4.81(m, 2H), 4.31-4.16 (m, 3H), 3.96 (s, 6H), 3.93-3.84 (m, 2H), 3.82-3.72(m, 3H), 3.59 (dd, J = 13.3, 6.7 Hz, 1H), 1.91-1.85 (m, 2H), 1.70-1.63(m, 2H). Example 4.6 NT NT ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 6.72(brs, 1H), 439 6.69 (s, 1H), 6.63 (s, 1H), 6.35 (brs, 1H), 6.19 (d, J =17.1 Hz, 1H), 6.00 (dd, J = 17.0, 10.2 Hz, 1H), 5.89 (s, 1H), 5.55 (dd,J = 10.3, 1.5 Hz, 1H), 4.96-4.82 (m, 2H), 4.31- 4.17 (m, 2H), 3.96 (s,6H), 3.93-3.82 (m, 2H), 3.81- 3.71 (m, 2H), 3.66 (dd, J = 8.9, 5.3 Hz,1H), 3.63-3.51 (m, 2H), 2.82-2.69 (m, 1H), 2.13-2.00 (m, 1H), 1.77- 1.72(m, 1H). Example 8.2 15.9 70.8 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H),6.73 (s, 1H), 443 6.63 (s, 1H), 6.24-6.16 (m, 1H), 6.13 (brs, 1H), 5.96(dd, J = 17.2, 10.3 Hz, 1H), 5.79 (brs, 1H), 5.59-5.51 (m, 1H),4.95-4.84 (m, 2H), 4.71 (s, 1H), 4.30-4.15 (m, 2H), 4.13-4.04 (m, 1H),4.05-3.98 (m, 1H), 3.97 (s, 6H), 3.92-3.82 (m, 3H), 3.76 (dd, J = 9.3,5.7 Hz, 1H), 2.45- 2.31 (m, 1H), 2.18-2.05 (m, 1H). Example 7.0 NT NT ¹HNMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.70 (s, 1H), 444 6.63 (s, 1H),6.42-6.33 (m, 1H), 6.20 (dd, J = 17.0, 1.4 Hz, 1H), 6.17-6.13 (m, 1H),5.97 (dd, J = 17.0, 10.3 Hz, 1H), 5.75 (d, J = 6.5 Hz, 1H), 5.57 (dd, J= 10.4, 1.4 Hz, 1H), 4.95-4.82 (m, 2H), 4.29-4.18 (m, 3H), 4.03-3.98 (m,2H), 3.97 (s, 6H), 3.89 (dd, J = 9.6, 3.6 Hz, 1H), 3.76 (dd, J = 9.3,5.8 Hz, 1H), 3.58-3.48 (m, 2H), 2.24-2.10 (m, 2H), 1.73-1.64 (m, 2H).Example 42.2 20.3 53.3 ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 6.88(brs, 1H), 452 6.77 (s, 1H), 6.64 (s, 1H), 6.17 (d, J = 16.8 Hz, 1H),5.95 (m, 2H), 5.55 (d, J = 10.2 Hz, 1H), 5.02-4.94 (m, 1H), 4.90 (s,1H), 4.46 (s, 1H), 4.31-4.18 (m, 2H), 3.97 (s, 6H), 3.91 (d, J = 10.8Hz, 1H), 3.73 (t, J = 8.1 Hz, 1H), 3.11 (s, 2H), 2.80 (s, 1H), 2.69 (s,1H). Example 66.9 40.8 89.2 ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 6.67(s, 1H), 454 6.63 (s, 1H), 6.21 (d, J = 17.0 Hz, 1H), 6.09-5.97 (m, 1H),5.57 (d, J = 10.2 Hz, 1H), 4.89-4.81 (m, 2H), 4.27- 4.20 (m, 2H), 3.96(s, 6H), 3.92-3.90 (m, 1H), 3.81- 3.77 (m, 1H), 3.59-3.48 (m, 2H), 2.30(dd, J = 15.2, 7.9 Hz, 1H), 1.83-1.76 (m, 2H), 1.59 (brd, J = 31.7 Hz,4H), 1.28 (brs, 3H). Example 82.4 163 299 ¹H NMR (400 MHz, CDCl₃) δ 8.87(s, 1H), 7.47-7.11 456 (m, 6H), 6.70 (s, 1H), 6.63 (s, 1H), 6.22 (d, J =17.1 Hz, 2H), 6.09-5.75 (m, 2H), 5.58 (d, J = 10.3 Hz, 1H), 4.89- 4.60(m, 2H), 4.22-4.15 (m, 2H), 3.96 (s, 6H), 3.83-3.75 (m, 3H), 3.03 (q, J= 6.8 Hz, 2H). Example 17.3 23.8 58.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02(s, 1H), 7.58 (s, 459 1H), 7.38 (s, 1H), 6.98 (s, 1H), 6.71 (s, 1H),6.14 (dd, J = 17.1, 10.2 Hz, 1H), 5.94 (dd, J = 17.2, 2.2 Hz, 1H), 5.47(dd, J = 10.4, 2.0 Hz, 1H), 4.86 (s, 1H), 4.67 (q, J = 6.1 Hz, 1H), 4.39(td, J = 14.6, 13.6, 5.3 Hz, 2H), 4.12 (t, J = 7.9 Hz, 1H), 4.02 (dd, J= 8.8, 6.5 Hz, 1H), 3.97 (s, 6H), 3.81-3.68 (m, 4H), 3.66 (dd, J = 8.8,5.9 Hz, 1H), 3.33 (s, 3H). Example 14.5 24.6 38.3 ¹H NMR (400 MHz,CDCl₃) δ 8.89 (s, 1H), 6.66 (s, 1H), 462 6.64 (s, 1H), 6.62 (s, 1H),6.30 (s, 1H), 6.23 (dd, J = 16.9, 1.4 Hz, 1H), 6.01 (dd, J = 16.9, 10.3Hz, 1H), 5.84 (s, 1H), 5.59 (dd, J = 10.3, 1.4 Hz, 1H), 4.93-4.77 (m,2H), 4.29- 4.19 (m, 2H), 3.96 (s, 6H), 3.91 (dd, J = 9.5, 4.0 Hz, 1H),3.79 (dd, J = 9.3, 5.5 Hz, 1H), 3.51 (dd, J = 13.1, 6.5 Hz, 1H), 3.36(dd, J = 13.2, 5.9 Hz, 1H), 0.99 (s, 9H). Example 46.4 NT NT ¹H NMR (400MHz, CDCl₃) δ 8.87 (s, 1H), 6.67 (s, 1H), 465 6.62 (s, 1H), 6.18 (d, J =17.1 Hz, 1H), 6.06 (d, J = 10.1 Hz, 1H), 5.86 (s, 1H), 5.54 (d, J = 10.1Hz, 1H), 4.96- 4.83(m, 2H), 4.30-4.19 (m, 2H), 3.96 (s, 6H), 3.89 (dd, J= 9.6, 3.7 Hz, 1H), 3.81 (dd, J = 9.2, 5.6 Hz, 1H), 3.59 (s, 2H), 2.76(s, 2H), 2.53 (s, 6H), 1.26 (s, 4H). Example 62.0 131.9 677.8 ¹H NMR(400 MHz, CDCl₃) δ 8.89 (s, 1H), 7.03 (s, 1H), 475 6.83 (d, J = 2.8 Hz,1H), 6.54 (d, J = 2.8 Hz, 1H), 6.30 (s, 1H), 6.22 (dd, J = 16.8, 1.4 Hz,1H), 6.00 (dd, J = 16.9, 10.3 Hz, 1H), 5.82 (s, 1H), 5.61-5.53 (m, 1H),4.88 (q, J = 6.5, 6.0 Hz, 2H), 4.33-4.18 (m, 2H), 3.92 (s, 3H), 3.89 (s,1H), 3.84 (s, 3H), 3.81-3.73 (m, 1H), 3.58-3.40 (m, 2H), 1.26 (s, 1H),0.66-0.46 (m, 2H), 0.42-0.24 (m, 2H). Example 8797 2393 >10000 ¹H NMR(400 MHz, CDCl₃) δ 9.18 (s, 1H), 7.71 (d, J = 4.2 498 Hz, 1H), 7.53 (d,J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 6.17 (d, J = 16.9 Hz, 1H),6.06 (d, J = 11.2 Hz, 1H), 5.55 (d, J = 10.1 Hz, 1H), 4.95 (s, 1H), 4.63(s, 1H), 4.39 (s, 2H), 4.31 (t, J = 6.7 Hz, 1H), 4.24 (s, 2H), 3.98 (s,6H), 3.92 (s, 1H), 0.88 (t, J = 7.0 Hz, 1H), 0.76-0.65 (m, 2H), 0.47 (s,2H). Example 15.7 17.8 49.9 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.68(s, 1H), 501 6.64 (s, 1H), 6.17 (d, J = 16.7 Hz, 1H), 5.96 (d, J = 12.1Hz, 1H), 5.55 (d, J = 10.5 Hz, 1H), 4.75-4.60 (m, 1H), 4.40-4.25 (m,1H), 4.10-4.02 (m, 1H), 4.01-3.90 (m, 3H), 3.96 (s, 6H), 3.77 (d, J =11.9 Hz, 1H), 3.62 (t, J = 12.2 Hz, 2H), 1.98-1.86 (m, 2H), 0.88 (s,1H), 0.55 (s, 2H), 0.35 (s, 2H). Example 29 75.2 115.9 ¹H NMR (400 MHz,CDCl₃) δ 8.87 (s, 1H), 6.67 (s, 1H), 510 6.62 (s, 1H), 6.48 (s, 1H),6.20 (dd, J = 16.9, 1.4 Hz, 2H), 6.05 (d, J = 8.5 Hz, 1H), 5.91 (dd, J =16.9, 10.3 Hz, 1H), 5.54 (d, J = 10.4, 1.4 Hz, 1H), 4.70 (d, J = 8.7 Hz,1H), 4.38-4.27 (m, 1H), 4.12-4.05 (m, 1H), 3.99 (d, J = 11.2 Hz, 1H),3.96 (s, 6H), 3.75 (dd, J = 12.0, 1.7 Hz, 1H), 3.65- 3.57 (m, 1H), 3.09(d, J = 5.0 Hz, 3H), 1.97-1.86 (m, 2H). Example 23.4 25.7 41.1 ¹H NMR(400 MHz, CDCl₃) δ 9.18 (s, 1H), 7.44 (s, 1H), 606 6.67 (s, 1H),6.30-6.24 (m, 1H), 6.17-6.08 (m, 1H), 5.63 (d, J = 10.7 Hz, 1H), 4.93(s, 2H), 4.35-4.30 (m 1H), 4.25 (dd, J = 9.4, 6.1 Hz, 1H), 3.97 (s, 6H),3.92 (dd, J = 9.6, 3.1 Hz, 1H), 3.87-3.82 (m, 1H), 2.98 (s, 3H). ExampleNT 36.6 56.1 ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 1H), 6.64 (s, 1H), 6096.55 (s, 1H), 6.25 (d, J = 16.8 Hz, 1H), 6.05 (dd, J = 16.9, 10.3 Hz,1H), 5.86 (brs, 1H), 5.62 (dd, J = 10.3, 1.4 Hz, 1H), 4.90-4.87 (m, 2H),4.82-4.78 (m, 1H), 4.31 (td, J = 10.3, 6.2 Hz, 2H), 3.97 (s, 6H),3.95-3.68 (m, 2H), 3.28-3.24 (m, 1H), 1.27-1.21 (m, 2H), 1.10 (dd, J =8.3, 3.0 Hz, 2H). Example 2.9 2.6 4.0 ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s,1H), 8.53 (s, 1H), 629 8.49 (s, 1H), 7.37 (s, 1H), 6.68 (s, 1H), 6.43(d, J = 6.2 Hz, 1H), 6.20 (d, J = 16.9 Hz, 1H), 6.09 (s, 1H), 5.98 (dd,J = 17.0, 10.2 Hz, 1H), 5.57 (d, J = 10.3 Hz, 1H), 4.97-4.90 (m, 2H),4.33-4.23 (m, 2H), 3.98 (s, 9H), 3.94 (dd, J = 9.8, 3.2 Hz, 1H), 3.82(dd, J = 9.5, 4.8 Hz, 1H). Example 4.2 10.1 17.3 ¹H NMR (400 MHz,Methanol-d₄) δ 9.03 (s, 1H), 8.56 (s, 637 1H), 8.40 (s, 1H), 7.49 (s,1H), 6.74 (t, J = 8.0 Hz, 1H), 6.03 (d, J = 5.9 Hz, 2H), 5.46 (t, J =5.9 Hz, 1H), 4,87 (s, 2H), 4.20 (4, J = 7.8 Hz, 1H), 4.12 (dd, J = 9.1,6.6 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 6H), 3.83 (d, J = 4.0 Hz, 1H), 3.74(dd, J = 9.2, 5.4 Hz, 1H). Example 8.0 28.0 68.4 ¹H NMR (400 MHz, CDCl₃)δ 8.88 (s, 1H), 6.74 (s, 1H), 655 6.70 (s, 1H), 6.62 (s, 1H), 6.19 (dd,J = 16.9, 1.4 Hz 2H), 5.95 (dd, J = 16.9, 10.3 Hz, 1H), 5.79 (s, 1H),5.55 (dd, J = 10.3, 1.4 Hz, 1H), 4.93-4.81 (m, 2H), 4.29-4.17 (m, 2H),3.96 (s, 6H), 3.88 (dd, J = 9.7, 3.3 Hz, 1H), 3.75 (dd, J = 9.2, 5.9 Hz,1H), 3.01-2.84 (m, 1H), 0.87-0.79 (m, 2H), 0.76-0.69 (m, 1H), 0.68-0.58(m, 1H). Example 6.5 9.6 13.3 ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H),6.69 (s, 1H), 657 6.62 (s, 1H), 6.26 (dd-J = 16.8, 1.3 Hz, 2H), 6.06(dd, J = 17.0, 10.3 Hz, 1H), 5.70-5.60 (n, 2H), 4.80-4.70 (m, 31-1),4.60-4.45 (m, 3H), 4.29-4.15 (m, 2H), 3.95 (s, 6H), 3.87-3.73 (m, 2H),2.42 (q, J = 7.6 Hz, 2H). Example 4.8 11.4 15.1 ¹H NMR (400 MHz, CDCl₃)δ 8.89 (s, 1H), 6.73 (s, 1H), 658 6.63 (s, 1H), 6.24 (d, J = 16.8 Hz,1H), 6.13 (d, J = 10.9 Hz, 1H), 5.61 (d, J = 10.1 Hz, 1H), 4.84-4.57 (m,4H), 4.54-4.07 (m, 5H), 3.95 (s, 6H), 3.89-3.72 (m, 2H), 3.30 (s, 3H).Example 6.6 18.0 24.3 ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 6.93 (s,1H), 659 6.68 (t, J = 7.9 Hz, 1H), 6.34 (brs, 1H), 6.24 (dd, J = 16.8,1.4 Hz, 1H), 6.05 (dd, J = 16.9, 10.3 Hz, 1H), 5.74 (brs, 1H), 5.62 (dd,J = 10.2, 1.4 Hz, 1H), 4.88-4.61 (m, 4H), 4.45-4.37 (m, 3H), 4.28-4.15(m, 2H), 3.91 (s, 6H), 3.84 (dd, J = 9.5, 3.6 Hz, 1H), 3.77 (dd, J =9.5, 5.1 Hz, 1H), 3.33 (s, 3H). Example 4.5 2.3 3.5 ¹H NMR (400 MHz,CDCl₃) δ 8.95 (s, 1H), 6.88 (s, 1H), 663 6.64 (s, 1H), 6.25 (d, J = 16.9Hz, 2H), 6.06 (dd, J = 17.0, 10.3 Hz, 1H), 5.93 (s, 1H), 5.63 (d, J =10.3 Hz, 1H), 4.88- 4.77 (m, 6H), 4.22 (dd, J = 9.5, 6.2 Hz, 2H), 3.96(s, 6H), 3.82 (ddd, J = 17.2, 9.6, 5.0 Hz, 2H). Example 4.9 3.7 4.9 ¹HNMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.06 (d, J = 664 8.1 Hz, 1H),7.23 (brs, 1H), 6.97 (s, 1H), 6.77 (s, 1H), 6.23 (dd, J = 17.1, 10.2 Hz,1H), 6.02 (dd, J = 17.1, 2.1 Hz, 1H), 5.57 (d, J = 10.7 Hz, 1H), 5.55(s, 1H), 4.74-4.58 (m, 2H), 4.21 (brs, 4H), 4.12-4.01 (m, 2H), 3.95 (s,6H), 3.78- 3.66 (m, 2H), 1.46 (s, 3H). Example 5.7 9.9 11.8 ¹H NMR (400MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.06 (d, J = 665 8.3 Hz, 1H), 7.28 (s,1H), 6.97 (s, 1H), 6.81 (s, 1H), 6.21 (dd, J = 17.1, 10.2 Hz, 1H), 6.00(dd, J = 17.1, 2.2 Hz, 1H), 5.54 (dd, J = 10.1, 2.2 Hz, 1H), 4.76-4.60(m, 2H), 4.17 (br s, 4H), 4.09 (d, J = 7.4 Hz, 1H), 4.05-4.00 (m, 1H),3.95 (s, 6H), 3.75 (dd, J = 8.7, 5.9 Hz, 1H), 3.67 (dd, J = 9.0, 5.2 Hz,1H), 3.21 (s, 3H), 1.49 (s, 3H). Example 4.5 3.2 4.6 ¹H NMR (400 MHz,CDCl₃) δ 8.90 (s, 1H), 6.93 (s, 1H), 666 6.68 (t, J = 7.9 Hz, 1H), 6.37(s, 1H), 6.24 (d, J = 16.9 Hz, 1H), 6.04 (dd, J = 17.0, 10.3 Hz, 1H),5.78 (s, 1H), 5.61 (d, J = 10.3 Hz, 1H), 4.84-4.73 (m, 2H), 4.56-4.41(m, 2H), 4.41-4.26 (m, 2H), 4.26-4.17 (m, 2H), 3.91 (s, 6H), 3.85 (dd, J= 9.6, 3.5 Hz, 1H), 3.76 (dd, J = 9.4, 5.1 Hz, 1H), 3.30 (s, 3H), 1.56(s, 3H). Example 14.7 16 22.6 ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1H),6.70 (s, 1H), 668 6.66 (s, 1H), 6.56 (s, 1H), 6.16 (d, J = 17.0 Hz, 1H),6.01 (dd, J = 17.1, 10.2 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H),4.80-4.55(m, 8H), 4.18-4.15 (m, 2H), 3.88 (s, 6H), 3.84- 3.70 (m, 4H).Example 11.0 6.2 8.7 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.71 (s,1H), 675 6.63 (s, 1H), 6.38 (brs, 1H), 6.24 (d, J = 16.9 Hz, 1H), 6.05(dd, J = 16.9, 10.2 Hz, 1H), 5.78 (brs, 1H), 5.61 (dd, J = 10.2, 1.3 Hz,1H), 4.87-4.75 (m, 2H), 4.42-4.15 (m, 6H), 3.95 (s, 6H), 3.86 (dd, J =9.5, 3.9 Hz, 1H), 3.78 (dd, J = 9.4, 5.4 Hz, 1H), 3.72-3.60 (m, 4H),1.86 (t, J = 5.2 Hz, 4H). Example 7.4 3.7 5.3 ¹H NMR (400 MHz, CDCl₃) δ8.80 (s, 1H), 6.63 (s, 1H), 677 6.54 (s, 1H), 6.41 (brs, 1H), 6.21 (d, J= 17.0 Hz, 1H), 5.99 (dd, J = 16.6, 10.2 Hz, 1H), 5.71 (brs, 1H), 5.53(dd, J = 10.3, 3.5 Hz, 1H), 4.85-4.70 (m, 2H), 4.28-3.96 (m, 7H), 3.88(s, 6H), 3.90-3.82 (m, 1H), 3.80-3.72 (m, 1H), 3.29 (d, J = 2.8 Hz, 3H),2.07-1.94 (m, 2H). Example 6.5 13.3 16.5 ¹H NMR (400 MHz, CDCl₃) δ 8.92(s, 1H), 6.94 (s, 1H), 678 6.56 (s, 1H), 6.50 (d, J = 7.4 Hz, 1H), 6.18(d, J = 16.9 Hz, 1H) 5.98 (dd, J = 16.9, 10.3 Hz, 2H), 5.54 (d, J = 9.7Hz, 1H), 4.82-4.69 (m, 2H), 4.74-4.64 (m, 2H), 4.19-4.12 (m, 2H), 3.89(s, 6H), 3.87-3.76 (m, 7H), 3.76-3.67 (m, 1H), 2.20-2.10 (m, 1H),2.08-1.95 (m, 1H). Example 8.2 5.4 8.8 ¹H NMR (400 MHz, CDCl₃) δ 8.92(s, 1H), 6.94 (s, 1H), 686 6.56 (s, 1H), 6.50 (d, J = 7.4 Hz, 1H), 6.18(d, J = 16.9 Hz, 1H), 5.98 (dd, J = 16.9, 10.3 Hz, 1H), 5.54 (d, J =10.2 Hz, 1H), 4.81-4.73 (m, 1H), 4.70-4.67 (m, 1H), 4.20-4.12 (m, 2H),3.89 (s, 6H), 3.88-3.67 (m, 10H), Example 6.3 6.9 10.0 ¹H NMR (400 MHz,CDCl₃) δ 9.03 (s, 1H), 7.25 (s, 1H), 687 6.70 (t, J = 7.9 Hz, 1H), 6.47(brs, 1H), 6.25 (d, J = 16.9 Hz 1H), 6.06 (dd, J = 16.9, 10.2 Hz, 1H),5.62 (d, J = 10.3 Hz, 1H), 4.88-4.81 (m, 1H), 4.78 (brs, 1H), 4.23 (dd,J = 9.5, 6.2 Hz, 2H), 3.93 (s, 6H), 3.92-3.81 (m, 9H), 3.81- 3.77 (m,1H). Example 8.0 8.4 12.1 ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 6.99(s, 1H), 690 6.64 (s, 1H), 6.55 (d, J = 7.1 Hz, 1H), 6.26 (dd, J = 17.1,1.3 Hz, 1H), 6.11-6.04 (m, 1H), 6.04 (s, 1H), 5.63 (d, J = 10.2 Hz, 1H),4.86-4.73 (m, 2H), 4.68 (d, J = 12.8 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H),4.29-4.20 (m, 2H), 3.97 (s, 6H), 3.94-3.85 (m, 3H), 3.82 (dd, J = 9.4,5.0 Hz, 1H), 2.79-2.68 (m, 2H), 1.23 (dd, J = 6.3, 2.2 Hz, 6H). Example5.6 1.3 2.1 ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 6.99 (s, 1H) 6936.63 (s, 1H), 6.53 (s, 1H), 6.23 (d, J = 16.9 Hz, 1H), 6.06 (dd, J =17.0, 10.2 Hz, 1H), 5.94 (s, 1H), 5.60 (d, J = 10.2 Hz, 1H), 4,87-4.77(m, 2H), 4.39 (d, J = 8.3 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 4.27-4.20(m, 2H), 3.96 (s, 6H), 3.88 (dd, J = 9.5, 3.5 Hz, 1H), 3.81 (dd, J =14.4, 5.1 Hz, 1H), 3.51-3.39 (m, 3H), 3.38 (s, 3H), 2.15-2.01 (m, 2H),1.79-1.74 (m, 2H). Example 4.8 10.0 12.0 ¹H NMR (400 MHz, CDCl₃) δ 9.01(s, 1H), 6.70 (t, J = 7.9 694 Hz, 1H), 6.22 (d, J = 16.8 Hz, 1H), 6.07(dd, J = 17.0, 10.2 Hz, 1H), 5.59 (d, J = 10.2 Hz, 1H), 4.86-4.80 (m,2H), 4.38-4.21 (m, 4H), 3.93 (s, 6H) 3.91-3.82 (m, 2H), 3.52-3.43 (m,3H), 3.39 (s, 3H), 2.21-2.11 (m, 2H). Example 8.5 17.2 20.2 1H NMR (400MHz, CDCl₃) δ 8.92 (s, 1H), 6.76 (s, 1H), 704 6.65 (brs, 1H), 6.62 (s,1H), 6.25 (d, J = 16.9 Hz, 1H), 6.05 (dd, J = 16.8, 10.4 Hz, 1H), 5.61(d, J = 10.3 Hz, 1H), 4.69 (brs, 1H), 4.55 (brs, 1H), 4.46-4.23 (m, 5H),4.10-3.99 (m, 2H), 3.95 (s, 6H), 3.74 (d, J = 11.9 Hz, 1H), 3.61 (t, J =11.8 Hz, 1H), 3.32 (s, 3H), 2.10-1.98 (m, 1H), 1.90- 1.80 (m, 1H).Example 62.7 1917.5 1917.5 ¹H NMR (400 MHz, CDCl₃) δ 10.71 (s, 1H), 9.63(s, 1H), 715 9.60 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 6.72 (s, 1H),6.49 (d, J = 16.7 Hz, 1H), 6.40 (dd, J = 16.9, 9.7 Hz, 1H), 5.84 (d-J =9.7 Hz, 1H), 5.21 (t, J = 6.0 Hz, 2H), 4.00 (s, 7H), 3.89 (t, J = 5.9Hz, 2H), 3.35 (s, 3H). Example 78.5 338.1 1211.5 ¹H NMR (400 MHz,DMSO-d₆) δ 9.75 (s, 1H), 9.71 (s, 723 1H), 9.68 (s, 1H), 8.37 (s, 1H),8.21 (s, 1H), 8.05 (s, 1H), 7.15 (s, 1H), 6.51 (dd, J = 17.0, 10.2 Hz,1H), 6.26 (dd, J = 17.1, 2.2 Hz, 1H), 5.75 (dd, J = 10.1, 2.1 Hz, 1H),4.56 (t, J = 5.6 Hz, 2H), 4.06 (s, 6H), 3.70 (t, J = 5.6 Hz, 2H), 3.14(s, 3H), Example 115.0 164 194 ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H),7.68 (s, 1H), 730 7.40 (s, 1H), 6.65 (s, 1H), 6.38-6.32 (m, 1H),6.27-6.21 (m, 1H), 5.73-5.69 (m, 1H), 5.30 (s, 1H), 4.81 (d, J = 5.6 Hz,2H), 3.96 (s, 6H), 3.78 (s, 3H). Example 990.9 1712 2631 ¹H NMR (400MHz, CDCl₃) δ 8.82 (s, 1H), 6.68 (s, 1H), 752 6.66 (s, 1H), 6.59 (s,1H), 6.13 (dd, J = 16.8, 1.4 Hz, 1H), 5.94 (dd, J = 17.0, 10.2 Hz, 1H),5.51 (dd, J = 10.3, 1.4 Hz, 1H), 5.30 (s, 1H), 4.96-4.82 (m, 1H), 4.42(s, 1H), 4.26 (dd, J = 9.8, 6.0 Hz, 1H), 4.18 (dd, J = 9.3, 7.4 Hz, 1H),3.92 (s, 6H), 3.88-3.81 (m, 1H), 3.74 (dd, J = 9.2, 6.9 Hz, 1H), 3.13(d, J = 4.6 Hz, 3H). Example 19 130 212 ¹H NMR (400 MHz, Methanol-d₄) δ9.22 (s, 1H), 7.65 (s, 753 1H), 6.94 (s, 1H), 6.19 (dd, J = 17.1, 9.9Hz, 1H), 6.10 (dd, J = 17.1, 2.2 Hz, 1H), 5.56 (dd, J = 9.9, 2.1 Hz,1H), 5.01 (s, 2H), 4.29 (s, 1H), 4.17 (dd, J = 9.3, 6.2 Hz, 1H), 3.98(s, 6H), 3.93-3.85 (m, 1H), 3.85-3.79 (m, 1H). Example 13.6 18.0 54.0 ¹HNMR (400 MHz, CDCl₃) δ 9.06 (d, J = 6.5 Hz, 1H), 754 7.11 (s, 1H), 6.64(s, 1H), 6.25 (dd, J = 16.9, 1.5 Hz, 1H), 6.05 (dd, J = 17.0, 10.4 Hz,1H), 5.60 (dd, J = 10.3, 1.5 Hz, 1H), 4.91 (brs, 1H), 4.79 (t, J = 6.5,1H), 4.59 (q, J = 7.0, 2H), 4.35-4.19 (m, 2H), 3.93-3.68 (m, 2H) 1.48(t, J = 7.1 Hz, 3H). Example 43.0 NT NT ¹H NMR (400 MHz, CDCl₃) δ 8.84(s, 1H), 6.84 (s, 1H), 755 6.67 (s, 1H), 6.58-6.49 (m, 3H), 6.30 (d, J =8.5 Hz, 2H), 6.10 (d, J = 17.0 Hz, 2H), 6.04-5.83 (m, 2H), 5.48 (d, J =10.1 Hz, 1H), 4.72 (s, 3H), 4.63 (d, J = 14.8 Hz, 1H), 4.17- 4.04 (m,2H), 3.89 (s, 6H), 3.78 (d, J = 6.2 Hz, 1H), 3.71 (s, 2H), 3.68 (s, 7H).Example 20.2 19 31 ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 7.43 (s, 1H),756 7.13 (s, 1H), 6.66 (s, 1H), 6.36 (s, 1H), 6.26 (dd, J = 16.9, 1.4Hz, 1H), 6.04 (dd, J = 16.9, 10.3 Hz, 1H), 5.94 (s, 1H), 5.63 (dd, J =10.3, 1.4 Hz, 1H), 4.89-4.78 (m, 2H), 4.45 (d, J = 2.8 Hz, 2H),4.31-4.21 (m, 2H), 3.97 (s, 6H), 3.95- 3.92 (m, 2H), 3.90-3.87 (m, 1H),3.81 (dd, J = 9.5, 4.8 Hz, 1H), 2.94-2.77 (m, 2H). Example 5.9 5.8 9.2¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.71 (s, 1H), 758 6.62 (s, 1H),6.42 (s, 1H), 6.20 (d, J = 17.0 Hz, 1H), 6.03- 5.91 (m 2H), 5.56 (d J =10.3 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.81 (s, 1H), 4.67 (s, 1H), 4.41(s, 1H), 4.25-4.05 (m, 3H), 4.25-4.12 (m, 3H), 3.97-3.80 (m, 10H), 3.68(s, 3H). Example 5.7 42.2 61.1 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J =11.1 Hz, 1H), 759 6.69 (s, 1H), 6.61 (s, 1H), 6.35-6.09 (m, 2H), 5.94(dd, J = 17.0, 10.3 Hz, 1H), 5.59 (d, J = 10.1 Hz, 2H), 5.00 (p, J = 7.5Hz, 1H), 4.83 (s, 1H), 4.31-4.18 (m, 1H), 4.16 (d, J = 8.1 Hz, 1H),4.01-3.85 (m, 12H), 3.67 (d, J = 14.5 Hz, 2H). Example 2.9 5.5 6.7 ¹HNMR (400 MHz, CDCl₃) δ 8.86 (d, J = 5.2 Hz, 1H), 760 6.68 (d, J = 10.6Hz, 1H), 6.61 (s, 1H), 6.42-6.21 (m, 1H), 6.14 (t, J = 18.1 Hz, 1H),6.00-5.78 (m, 1H), 5.74 (s, 1H), 5.49 (dd, J = 29.1, 10.3 Hz, 1H), 4.91(t, J = 7.6 Hz, 1H), 4.87-4.78 (m, 1H), 4.52-4.40 (m, 1H), 4.24-4.14 (m,2H), 4.08 (d, J = 8.7 Hz, 1H), 3.95 (s, 6H), 3.92-3.83 (m, 2H),3.80-3.70 (m, 2H), 2.03-1.89 (m, 2H), 1.54- 1.43 (m, 3H). Example 14.320.7 51.8 ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.64 (s, 1H), 761 8.53(s, 1H), 7.74 (s, 1H), 6.88 (d, J = 2.7 Hz, 1H), 6.61 (d, J = 2.7 Hz,1H), 6.20 (d J = 16.9 Hz, 1H), 6.01 (s, 1H), 5.56 (d, J = 10.3 Hz, 1H),5.01-4.91 (m, 2H), 4.32-4.23 (m, 2H), 4.02 (s, 3H), 3.99-3.95 (m, 1H),3.95 (s, 3H), 3.87 (s, 3H), 3.84-3.82 (m, 1H). Example 5.2 3.2 4.2 ¹HNMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 6.83 (s, 1H), 762 6.63 (s, 1H),6.30 (s, 1H), 6.22 (d, J = 17.1 Hz, 1H), 6.04 (dd, J = 16.9, 10.2 Hz,1H), 5.81 (s, 1H), 5.60 (d, J = 10.2 Hz, 1H), 4.87-4.80 (m, 1H),4.80-4.73 (m, 1H), 4.70 (d, J = 6.4 Hz, 2H), 4.60 (d, J = 13.8 Hz, 2H),4.27 (d, J = 13.6 Hz, 1H), 4.23-4.15 (m, 2H), 4.10 (d, J = 13.7 Hz, 1H),3.96 (s, 6H), 3.86 (dd, J = 9.6, 4.0 Hz, 1H), 3.75 (dd, J = 9.4, 5.8 Hz,1H), 3.23 (q, J = 7.2 Hz, 1H), 2.08 (d, J = 8.6 Hz, 1H). Example 7.9 7.811.1 ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 6.79 (s, 1H), 763 6.63 (s,1H), 6.25 (dd, J = 23.9, 17.1 Hz, 2H), 5.63 (dd, J = 19.8, 10.3 Hz, 2H)4.76 (s, 2H) 4.66 (s, 1H), 4.22 (dd, J = 15.1, 7.2 Hz, 3H), 4.4-4.10 (m,1H), 3.97 (d, J = 2.0 Hz, 8H), 3.85 (d, J = 10.5 Hz, 3H), 3.75 (s, 1H),2.00 (d, J = 9.2 Hz, 1H), 1.93 (s, 1H). Example 7.0 49.4 60.4 ¹H NMR(400 MHz, CDCl₃) δ 8.78 (s, 1H), 6.84 (brs, 2H), 764 6.76 (s, 1H), 6.58(t J = 7.9 Hz, 1H), 6.39 (brs, 1H), 6.08 (d J = 16.9 Hz, 1H), 5.93 (dd,J = 17.0, 10.2 Hz, 1H), 5.39 (d, J = 10.2 Hz, 1H), 4.81 (p, J = 6.6, 5.6Hz, 2H), 4.15- 4.05 (m, 2H), 3.85-3.81 (m, 1H), 3.81 (s, 6H), 3.71 (dd,J = 9.2, 5.8 Hz, 1H), 3.08 (s, 3H). Example 158 420.8 656.5 ¹H NMR (400MHz, CDCl₃) δ 8.93 (s, 1H), 6.80 (s, 1H), 765 6.64 (s, 1H), 6.23 (d, J =16.9 Hz, 1H), 6.08-5.91 (m, 4H), 5.75 (s, 1H), 5.58 (d, J = 10.4 Hz,1H), 4.89 (s, 2H), 4.24 (ddd, J = 23.7, 9.4, 5.9 Hz, 2H), 3.96 (s, 6H),3.88 (dd, J = 9.8, 3.4 Hz, 1H), 3.76 (dd, J = 9.2, 5.5 Hz, 1H). Example8.3 19.8 27.9 ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 6.60 (s, 1H), 7666.54 (s, 1H), 6.33 (brs, 1H), 6.12 (d, J = 16.9 Hz, 1H), 5.96 (dd, J =17.0, 10.3 Hz, 1H), 5.48 (dd, J = 10.3, 1.4 Hz, 1H), 4.83-4.78 (m, 2H),4.17-4.06 (m, 2H), 3.84-3.81 (m,1H), 3.71-3.68 (m, 1H). Example 7 23.945.1 ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 6.87 (s, 1H), 767 6.68 (t,J = 7.9 Hz, 1H), 6.60 (brs, 1H), 6.22 (s, 1H), 6.17 (s, 1H), 5.96 (dd, J= 16.9, 10.3 Hz, 1H), 5.80 (brs, 1H), 5.56 (d, J = 10.3 Hz, 1H),4.94-4.83 (m, 2H), 4.30-4.18 (m, 2H), 3.91 (s, 6H), 3.88 (s, 1H), 3.75(dd, J = 9.3, 5.9 Hz, 1H), 3.65 (s, 2H), 1.36 (t, J = 7.2 Hz, 3H).Example 4 9.9 12.5 ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 7.09 (s, 1H),768 6.69 (t, J = 7.9 Hz, 1H), 6.26 (dd, J = 17.0, 1.3 Hz, 1H), 6.14 (d,J = 7.4 Hz, 1H), 6.03 (dd, J = 17.0, 10.3 Hz, 1H), 5.75 (d, J = 7.1 Hz,1H), 5.63 (dd, J = 10.3, 1.3 Hz, 1H), 4.89-4.83 (m, 1H), 4.82-4.72 (m,5H), 4.23 (dd, J = 9.5, 6.2 Hz, 2H), 3.92 (s, 6H), 3.81 (ddd, J = 19.8,9.5, 4.8 Hz, 2H). Example 3.7 8.4 10.0 ¹H NMR (400 MHz, CDCl₃) δ 8.94(s, 1H), 7.04 (s, 1H), 769 6.69 (t, J = 7.8 Hz, 1H), 6.34 (brs, 1H),6.22 (d, J = 16.9 Hz, 1H), 6.04 (dd, J = 17.1, 10.1 Hz, 1H), 5.60 (d, J= 10.2 Hz, 1H), 4.87-4.70 (m, 4H), 4.63 (d, J = 13.5 Hz, 2H), 4.30 (d, J= 13.6 Hz, 1H), 4.23-4.10 (m, 3H), 3.92 (s, 6H), 3.90-3.85 (m, 1H),3.79-3.73 (m, 1H), 3.29-3.24 (m, 1H), 2.08-2.01 (m, 2H). Example2413.9 >10000 >10000 ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.78 (t, J= 7.5, 770 1H), 7.31 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.96 (t, J = 8.0Hz, 1H), 6.49 (m, 1H), 6.27 (brs, 1H), 6.18 (d, J = 16.9 Hz, 1H), 5.93(dd, J = 17.0, 10.3 Hz, 1H), 5.84, (brs, 1H), 5.53 (d, J = 10.3 Hz, 1H),4.91-4.88 (m, 2H), 4.31-4.13 (m, 2H), 3.94 (s, 3H), 3.94-3.88(m, 1H),3.82-3.70 (m, 1H), 3.21 (t, J = 4.8 Hz, 3H). Example 7.9 25.5 32.3 ¹HNMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 6.67 (s, 1H), 771 6.63 (s, 1H),6.22, (brs, 1H), 6.20 (dd, J = 17.0, 1.4 Hz, 1H), 5.97 (dd, J = 17.0,10.3 Hz, 1H), 5.79 (brs, 1H), 5.55 (dd, J = 10.3, 1.5 Hz, 1H), 4.94-4.86(m, 2H), 4.26-4.18 (m, 2H), 3.96 (s, 6H), 3.88 (dd, J = 9.8, 3.2 Hz,1H), 3.81- 3.72 (m, 1H). Example 2.9 6.8 8.1 ¹H NMR (400 MHz, CDCl₃) δ8.77 (s, 1H), 6.81 (s, 1H), 772 6.59 (s, 1H), 6.57(brs, 1H), 6.14 (d, J= 16.6 Hz, 1H), 5.96 (m, 1H), 5.85 (brs, 1H), 5.53 (d, J = 10.4 Hz, 1H),4.87- 4.66 (m, 2H), 4.53-4.23 (m, 4H), 4.18-4.08 (m, 2H), 3.83 (s, 6H),3.82-3.69 (m, 2H), 1.95-1.75 (m, 2H), 1.51 (s, 3H). Example 1.8 2.0 2.3¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H), 6.87 (d, J = 5.2 773 Hz, 1H),6.66 (t, J = 8.1 Hz, 1H), 6.45 (brs, 1H), 6.14 (dd, J = 16.9, 12.4 Hz,1H), 5.96 (dd, J = 16.9, 10.3 Hz, 1H), 5.82 (brs, 1H), 5.50 (d, J =20.2, 10.3 Hz, 1H), 4.93-4.85 (m, 1H), 4.84-4.78 (m, 1H), 4.43-4.34 (m,2H), 4.19-3.77 (m, 5H), 3.90 (s, 6H), 3.72-3.69 (m, 1H), 1.49 (d, J =23.8 Hz, 3H). Example 3.2 6.9 8.8 ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s,1H), 6.88 (s, 1H), 774 6.67 (t, J = 7.9 Hz, 1H), 6.52 (brs, 1H), 6.24(dd, J = 17.0, 1.5 Hz, 1H), 6.08 (dd, J = 17.0, 10.2 Hz, 1H), 5.96 (brs,1H), 5.61 (dd, J = 10.2, 1.4 Hz, 1H), 4.82-4.72 (m, 2H), 4.57 (brs, 4H),4.26-4.16 (m, 2H), 3.91 (s, 6H), 3.85 (dd, J = 9.4, 3.9 Hz, 1H), 3.78(dd, J = 9.4, 5.0 Hz, 1H), 2.42 (p, J = 7.6 Hz, 2H). Example 8.9 20.827.8 ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 6.96 (s, 1H), 775 6.69 (t,J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.25 (dd, J = 17.0, 1.4 Hz, 1H), 6.08 (s,1H), 6.02 (dd, J = 16.9, 10.3 Hz, 1H), 5.60 (dd, J = 10.3, 1.4 Hz, 1H),4.73 (brs, 1H, 4.56 (brs, 1H), 4.42 (d, J = 8.5 Hz, 1H), 4.39-4.22 (m,4H), 4.05 (dd, J = 12.0, 4.5 Hz, 1H), 3.99 (d, J = 11.7 Hz, 1H), 3.92(s, 6H), 3.75 (dd, J = 11.9, 1.6 Hz, 1H), 3.65-3.57 (m, 1H), 3.33 (s,3H), 2.09-2.02 (m, 1H), 1.91-1.81 (m, 1H). Example 4.9 7.9 9.4 ¹H NMR(400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.92 (s, 1H), 776 6.67 (t, J = 7.9 Hz,1H), 6.38 (brs, 1H), 6.23 (dd, J = 17.0, 1.4 Hz, 1H), 6.03 (dd, J =16.9, 10.3 Hz, 1H), 5.80 (brs, 1H), 5.61 (dd, J = 10.3, 1.4 Hz, 1H),4.86-4.77 (m, 2H), 4.27-4.19 (m, 6H), 3.91 (s, 6H), 3.89-3.86 (m, 1H),3.76 (dd, J = 9.3, 5.7 Hz, 1H), 3.69-3.66 (m, 4H), 1.86 (t, J = 5.2 Hz,4H). Example NT 650.8 660 ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H),6.86-6.81 (m, 777 3H), 6.45 (brs, 1H), 6.13 (d, J = 16.9 Hz, 1H), 6.06(brs, 1H), 5.86 (dd J = 16.9 10.3 Hz, 1H), 5.67 (brs, 1H), 5.49 (d, J =10.4 Hz, 1H), 4.98-4.68 (m, 2H), 4.28-4,07 (m, 2H), 3.84 (s, 3H),3.84-3.71 (m, 1H), 3.67 (dd, J = 9.2, 6.0 Hz, 1H), 3.08 (d, J = 4.8 Hz,3H). Example NT 9.5 11.2 ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 6.70(s, 1H), 778 6.61 (s, 1H), 6.29 (brs, 1H), 6.11 (d, J = 17.1 Hz, 1H),5.81 (m, 2H), 5.45 (d, J = 10.2 Hz, 1H), 5.07-4.84 (m, 2H), 4.55-4.40(m, 1H), 4.22-4.15 (m, 2H), 4.05-3.75 (m, 3H), 3.95 (s, 6H), 3.91-3.71(m, 2H), 2.05-1.96 (m, 2H), 1.44 (s, 3H). Example NT 7.5 8.6 ¹H NMR (400MHz, CDCl₃) δ 8.87 (s, 1H), 6.70 (s, 1H), 779 6.61 (s, 1H), 6.43 (brs,1H), 6.11 (d, J = 17.1 Hz, 1H), 5.97 (dd, J = 16.9, 10.3 Hz, 1H,), 5.79(brs, 1H), 5.45 (d, J = 10.2 Hz, 1H), 5.01-4.75 (m, 2H), 4.55-4.40 (m,1H), 4.25-4.00 (m, 4H), 3.95 (s, 6H), 3.94-4.80 (m, 2H), 3.79-3.72 (m,1H), 2.03-1.93 (m, 2H), 1.53 (s, 3H). Example 17.0 38.4 47.6 ¹H NMR (400MHz, CDCl₃) δ 8.87 (s, 1H), 6.86 (s, 1H), 786 6.68 (t, J = 7.9 Hz, 1H),6.49 (s, 1H), 6.20 (dd, J = 16.9, 1.3 Hz, 1H), 6.11 (s, 1H), 6.02 (d, J= 8.6 Hz, 1H), 5.88 (dd, J = 17.0, 10.3 Hz 1H) 5.53 (dd, J = 10.4, 1.4Hz, 1H), 4.73 (d, J = 8.5 Hz, 1H), 4.38-4.26 (m, 1H), 4.08 (d, J = 12.1Hz, 1H), 3.99 (d, J = 12.1 Hz, 1H), 3.92 (s, 6H), 3.75 (dd, J = 12.0,1.7 Hz, 1H), 3.61 (m, 1H), 3.13 (s, 3H), 1.91 (m, 2H). Example 45.0 86.0102.8 ¹H NMR (400 MHz, Methanol-d₄) δ 8.89 (s, 1H), 6.90 (t, 787 J = 8.1Hz, 1H), 6.81 (s, 1H), 6.13 (dd, J = 17.1, 1.9 Hz, 1H), 5.96 (dd, J =17.0, 10.3 Hz, 1H), 5.47 (dd, J = 10.2, 1.9 Hz, 1H), 4.24 (dt, J = 12.4,4.2 Hz, 1H), 4.07 (dd, J = 11.9, 4.4 Hz, 1H), 3.99-3.93 (m, 1H), 3.90(s, 6H), 3.78 (dd, J = 12.0, 2.0 Hz, 1H), 3.67-3.52 (m, 2H), 3.47-3.33(m, 1H), 2.06 (qd, J = 12.5, 4.8 Hz, 1H), 1.77-1.66 (m, 1H), 1.46-1.26(m, 5H). Example 7.8 12.6 15.9 ¹H NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H),7.24 (s, 1H), 789 7.00 (brs, 1H), 6.70 (t, J = 8.0 Hz, 1H), 6.25 (dd, J= 16.9, 1.3 Hz, 1H), 6.02 (dd, J = 17.0, 10.3 Hz, 1H), 5.57 (d, J = 10.3Hz, 1H), 4.50-4.30 (m, 2H), 4.19-3.76 (m, 11H), 3.97 (s, 6H), 3.63 (t, J= 10.2 Hz, 1H), 2.32-1.75(m, 2H). Example 8.5 11.4 13.6 ¹H NMR (400 MHz,CDCl₃) δ 8.93 (s, 1H), 6.97 (s, 1H), 790 6.68 (t, J = 7.9 Hz, 1H), 6.24(dd, J = 17.1, 1.4 Hz, 1H), 6.04 (brs, 1H), 6.01 (dd, J = 16.9, 10.3 Hz,1H), 5.63- 5.53 (m, 1H), 4.62-4.31 (m, 4H), 4.22-3.95 (m, 4H), 3.92 (s,6H), 3.78-3.72 (m, 1H), 3.66-3.57 (m, 1H), 3.28 (s, 3H), 1.13-2.05 (m,1H), 1.90-1.78 (m, 1H), 1.53 (s, 3H). Example 3.7 6.4 8.4 ¹H NMR (400MHz, CDCl₃) δ 8.97 (s, 1H), 7.10 (s, 1H), 791 6.70 (t, J = 7.9 Hz, 1H),6.48 (d, J = 7.2 Hz, 1H), 6.27 (dd, J = 17.0, 1.4 Hz, 1H), 6.18-6.08 (m,1H), 5.98 (dd, J = 16.9, 10.3 Hz, 1H), 5.59 (dd, J = 10.3, 1.3 Hz, 1H),4.80 (q, J = 12.0 Hz, 2H), 4.68 (q, J = 11.9 Hz, 2H), 4.44 (d, J = 10.0Hz, 1H), 4.41-4.34 (m, 1H), 4.06 (dd, J = 11.9, 4.6 Hz, 1H), 3.99 (d, J= 11.8 Hz, 1H), 3.92 (s, 6H), 3.76 (dd, J = 11.9, 1.6 Hz, 1H), 3.62 (td,J = 12.0, 2.5 Hz, 1H), 2.02 (s, 1H), 1.92-1.81 (m, 1H). Example 3.1 4.86.2 ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 6.92 (s, 1H), 792 6.83 (d, J= 6.8 Hz, 1H), 6.68 (t, J = 7.9 Hz, 1H), 6.26 (dd, J = 16.9, 1.5 Hz,1H), 6.07 (dd, J = 17.0, 10.2 Hz, 1H), 6.02 (brs, 1H),, 5.61 (dd, J =10.3, 1.5 Hz, 1H), 4.53 (s, 2H), 4.48-4.36 (m, 3H), 4.35-4.29 (m, 1H),4.05 (dd, J = 11.9, 4.6 Hz, 1H), 3.99 (d, J = 11.7 Hz, 1H), 3.91 (s,6H), 3.74 (dd, J = 11.8, 1.6 Hz, 1H), 3.61 (td, J = 12.0, 2.5 Hz, 1H),2.41-2.32 (m, 2H), 2.12-2.04 (m, 1H), 1.91-1.80 (m, 1H). Example 5.3 7.99.9 ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 6.97 (s, 1H), 793 6.67 (t, J= 7.9 Hz, 1H), 6.63 (brs, 1H), 6.23 (dd, J = 17.0, 1.3 Hz, 1H), 6.04 (d,J = 8.8 Hz, 1H), 5.99 (dd, J = 17.1, 10.4 Hz, 1H), 5.57 (dd, J = 10.2,1.4 Hz, 1H), 4.51-4.39 (m, 3H), 4.38-4.31 (m, 1H), 4.30-4.20 (m, 2H),4.07- 3.96 (m, 2H), 3.91 (s, 6H), 3.75 (dd, J = 11.8, 1.6 Hz, 1H),3.65-3.56 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.80 (m, 1H), 1.56 (s, 3H).Example 4.8 5.5 6.9 ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 3.0 Hz, 1H),794 6.93 (d, J = 4.0 Hz, 1H), 6.68 (t, J = 7.9 Hz, 1H), 6.36 (brs, 1H),6.26-6.15 (m, 1H), 6.05-5.90 (m, 2H), 5.60-5.50 (m, 1H), 4.50-4.30 (m,2H), 3.92 (s, 6H), 4.23-3.80 (m, 7H), 3.70-3.65 (m, 1H), 3.60-3.55 (m,1H), 3.34 (d, J = 7.0 Hz, 3H), 2.02-1.90 (m, 2H), 1.87-1.78 (m, 2H).Example 7.5 9.5 11.8 ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 7.20 (s,1H), 795 6.69 (t, J = 7.9 Hz, 1H), 6.22 (dd, J = 17.0, 1.5 Hz, 1H), 6.02(dd, J = 17.0, 10.3 Hz, 1H), 5.55 (d, J = 10.8 Hz, 1H), 4.54-4.15 (m,4H), 4.13-4.00 (m, 2H), 3.93 (s, 6H), 3.77 (d, J = 12.0 Hz, 1H),3.70-3.57 (m, 1H), 3.52-3.38 (m, 3H), 3.37 (s, 3H), 2.07-1.85 (m, 2H),1.65-1.46 (m, 4H). Example 23.0 38.0 47.8 ¹H NMR (400 MHz, CDCl₃) δ 8.95(s, 1H), 7.04 (s, 1H), 796 6.68 (t, J = 7.9 Hz, 1H), 6.25 (s, 1H), 6.20(dd, J = 17.0, 1.4 Hz, 1H), 6.07 (s, 1H), 5.93 (dd, J = 16.9, 10.3 Hz,1H), 5.56 (dd, J = 10.2, 1.4 Hz, 1H), 4.71 (d, J = 6.4 Hz, 2H), 4.61 (d,J = 13.6 Hz, 1H), 4.55 (d, J = 13.6 Hz, 1H), 4.45 (d, J = 8.9 Hz, 1H),4.41-4.34 (m, 1H), 4.17 (d, J = 13.7 Hz, 1H), 4.07 (d, J = 13.5 Hz, 2H),3.99 (d, J = 11.9 Hz, 1H), 3.92 (s, 6H), 3.73 (d, J = 11.6 Hz, 1H),3.67-3.64 (m, 1H), 3.59 (td, J = 11.9, 2.6 Hz, 1H), 3.22 (q, J = 7.1 Hz,1H), 1.97 (d, J = 13.7 Hz, 1H), 1.92-1.81 (m, 1H). BLU-9931 24.7 5491362 BLU-554  18.0 27 126 Note “NT”, i.e., “Not Tested”, means that thecompound is not tested. BLU-9931 and BLU-554 are positive compounds.

It can be seen from the enzymatic activity data of the compounds ofspecific examples that the compounds of the present invention have astrong inhibitory effect on FGFR4 kinase activity. It can be seen fromthe cell activity data of the compounds of specific examples that thecompounds of the present invention have a strong inhibitory effect onthe proliferation activity of HuH-7 cells highly expressing FGFR4.

All documents mentioned in the present application are herebyincorporated by reference in their entirety, just as each document iscited separately as a reference. In addition, it should be understoodthat various modifications and changes may be made by those skilled inthe art after reading the above teachings of the present invention andthese equivalent forms also fall within the scope defined by the claimsappended hereto.

The invention claimed is:
 1. A method for treating FGFR4 related cancercomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (IVa-1), a stereoisomer orpharmaceutically acceptable salt thereof:

wherein Z is

R₂, R₃, R₄ and R₅ are each independently selected from the groupconsisting of H, deuterium, Cl, F, hydroxyl, methyl, isopropyl,cyclopropyl, 3-oxacyclobutyl, trifluoromethyl, trideuteromethyl and—O—R₁₁, or R₂ and R₄, R₃ and R₅ are taken together with the directlyattached carbon atoms to form a 5-8 membered heterocyclyl, theheteroatom is N or 0; R₈ is selected from the group consisting of H,deuterium, halogen, cyano, nitro, azido, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, —C₀₋₈—S(O)_(r)R₁₀, —C₀₋₈—P(O)(R₁₀)₂, —C₀₋₈—O—R₁₁,—C₀₋₈—C(O)OR₁₁, —C₀₋₈—C(O)R₁₂, —C₀₋₈—O—C(O)R₁₂, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—C(O)NR₁₃R₁₄, —C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁, abovegroups are further optionally substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano, nitro,azido, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, 3-8 membered heterocyclyl, C₅₋₈ aryl, 5-8 memberedheteroaryl, —C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁,—C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄,—C₀₋₄—N(R₁₃)—C(O)R₁₂ and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are furthermore optionally substituted by one or more substituents selected fromthe group consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁; X₁ is —CH— or N; R₁₀ is selected from thegroup consisting of H, deuterium, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₈cycloalkyl, 3-10 membered heterocyclyl, C₁₋₈ haloalkyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, amino, mono-C₁₋₈ alkylamino, di-C₁₋₈ alkylamino andC₁₋₈ alkanoylamino; R₁₁ is selected from the group consisting of H,deuterium, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl and 5-10 membered heteroaryl, abovegroups are unsubstituted or substituted by one or more substituentsselected from the group consisting of deuterium, halogen, cyano, C₁₋₈alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₃₋₈ cycloalkyl, 3-10 memberedheterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₈ alkylsulfonyl,C₁₋₈ alkylsulfonylamino, amino, mono-C₁₋₈ alkylamino, di-C₁₋₈alkylamino, ═O or hydroxyl; R₁₂ is selected from the group consisting ofH, deuterium, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyloxy, 3-10 membered heterocyclyl, 3-10membered heterocyclyloxy, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₅₋₁₀aryloxy and 5-10 membered heteroaryloxy, above groups are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈alkylthio, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl, C₅₋₁₀ aryl, 5-10membered heteroaryl, C₁₋₈ alkylsulfonyl, C₁₋₈ alkylsulfonylamino, amino,mono-C₁₋₈ alkylamino, di-C₁₋₈ alkylamino, ═O or hydroxyl; R₁₃ and R₁₄are each independently selected from the group consisting of H,deuterium, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₈alkylsulfonyl and C₁₋₈ alkanoyl, or R₁₃ and R₁₄ are taken together withthe directly attached nitrogen atom to form a 4-10 memberedheterocyclyl, above groups are unsubstituted or substituted by one ormore substituents selected from the group consisting of deuterium,halogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₃₋₈ cycloalkyl, 3-10membered heterocyclyl, C₅₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₈alkylsulfonyl, C₁₋₈ alkylsulfonylamino, amino, mono-C₁₋₈ alkylamino,di-C₁₋₈ alkylamino, ═O or hydroxyl; r is 0, 1 or 2; wherein unlessotherwise defined, the heterocyclyl is a saturated or partiallyunsaturated monocyclic or polycyclic cyclic hydrocarbon substituentcontaining 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur,and the polycyclic cycloalkyl is a spiro, fused or bridged cycloalkyl,and the heteroaryl is a heteroaromatic system containing 1 to 2heteroatoms selected from nitrogen, oxygen or sulfur; and wherein theFGFR4 related cancer is prostate cancer, liver cancer, pancreaticcancer, esophageal cancer, gastric cancer, lung cancer, breast cancer,ovarian cancer, colon cancer, skin cancer, glioblastoma orrhabdomyosarcoma.
 2. The method of claim 1, wherein R₈ is selected fromthe group consisting of H, deuterium, halogen, cyano, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, 3-10 membered heterocyclyl,C₅₋₁₀ aryl, 5-10 membered heteroaryl, —C₀₋₈—O—R₁₁, —C₀₋₈—NR₁₃R₁₄,—C₀₋₈—N(R₁₃)—C(O)R₁₂ and —C₀₋₈—N(R₁₃)—C(O)OR₁₁, above groups are furtheroptionally substituted by one or more substituents selected from thegroup consisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8membered heterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl,—C₀₋₄—S(O)_(r)R₁₀, —C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂,—C₀₋₄—O—C(O)R₁₂, —C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂and —C₀₋₄—N(R₁₃)—C(O)OR₁₁, above groups are further more optionallysubstituted by one or more substituents selected from the groupconsisting of deuterium, halogen, cyano, nitro, azido, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, 3-8 memberedheterocyclyl, C₅₋₈ aryl, 5-8 membered heteroaryl, —C₀₋₄—S(O)_(r)R₁₀,—C₀₋₄—O—R₁₁, —C₀₋₄—C(O)OR₁₁, —C₀₋₄—C(O)R₁₂, —C₀₋₄—O—C(O)R₁₂,—C₀₋₄—NR₁₃R₁₄, —C₀₋₄—C(O)NR₁₃R₁₄, —C₀₋₄—N(R₁₃)—C(O)R₁₂ and—C₀₋₄—N(R₁₃)—C(O)OR₁₁.
 3. The method of claim 1, wherein the compound isselected from the group consisting of: